bims-ectoca 2022-02-27 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2022‒02‒27
25 papers selected by
Ankita Daiya
BITS Pilani

A genome-wide expression profile of noncoding RNAs in human osteosarcoma cells as they acquire resistance to cisplatin.
Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers.
Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer.
H3K27ac nucleosomes facilitate HMGN localization at regulatory sites to modulate chromatin binding of transcription factors.
The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression.
HiMoRNA: A Comprehensive Database of Human lncRNAs Involved in Genome-Wide Epigenetic Regulation.
Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors.
O-GlcNAcylation links oncogenic signals and cancer epigenetics.
Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma.
Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity.
Computational exploration of cellular communication in skin from emerging single-cell and spatial transcriptomic data.
HDAC9 Contributes to Serous Ovarian Cancer Progression through Regulating Epithelial-Mesenchymal Transition.
Evolutionary adaptation of the Polycomb repressive complex 2.
Tumor suppressive lncRNA MEG3 binds to EZH2 and enhances CXCL3 methylation in gallbladder cancer.
Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library.
Vault RNA1-1 riboregulates the autophagic function of p62 by binding to K7/R21 that are critical for p62 oligomerisation.
Diaphanous related formin 3 knockdown suppresses cell proliferation and metastasis of osteosarcoma cells.
Pan-cancer analysis of histone methyltransferase KMT2D with potential implications for prognosis and immunotherapy in human cancer.
The methyltransferase enzymes, KMT2D, SETD1B, and ASH1L, are key mediators of both metabolic and epigenetic changes during cellular senescence.
Localized Proteasomal Degradation: From the Nucleus to Cell Periphery.
circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis.
The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes.
Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes.
Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines.
Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions.

Discov Oncol. 2021 Oct 20. 12(1): 43

A genome-wide expression profile of noncoding RNAs in human osteosarcoma cells as they acquire resistance to cisplatin.

Harshita Sharma, Divya Niveditha, Rajdeep Chowdhury, Sudeshna Mukherjee, Shibasish Chowdhury.

  BACKGROUND: Recurrence after cisplatin therapy is one of the major hindrances in the management of cancer. This necessitates a deeper understanding of the molecular signatures marking the acquisition of resistance. We therefore modeled the response of osteosarcoma (OS) cells to the first-line chemotherapeutic drug cisplatin. A small population of nondividing cells survived acute cisplatin shock (persisters; OS-P). These cells regained proliferative potential over time re-instating the population again (extended persisters; OS-EP).RESULT: In this study, we present the expression profile of noncoding RNAs in untreated OS cells (chemo-naive), OS-P, OS-EP and drug-resistant (OS-R) cells derived from the latter. RNA sequencing was carried out, and thereafter, differential expression (log2-fold ± 1.5; p value ≤ 0.05) of microRNAs (miRNAs) was analyzed in each set. The core set of miRNAs that were uniquely or differentially expressed in each group was identified. Interestingly, we observed that most of each group had their own distinctive set of miRNAs. The miRNAs showing an inverse correlation in expression pattern with mRNAs were further selected, and the key pathways regulated by them were delineated for each group. We observed that pathways such as TNF signaling, autophagy and mitophagy were implicated in multiple groups.
CONCLUSION: To the best of our knowledge, this is the first study that provides critical information on the variation in the expression pattern of ncRNAs in osteosarcoma cells and the pathways that they might tightly regulate as cells acquire resistance.

Keywords:  Drug resistance; Drug tolerant persister; Osteosarcoma; RNA sequencing

DOI:  https://doi.org/10.1007/s12672-021-00441-6
Cancers (Basel). 2022 Feb 17. pii: 1029. [Epub ahead of print]14(4):

Assays Used for Discovering Small Molecule Inhibitors of YAP Activity in Cancers.

Subhajit Maity, Artem Gridnev, Jyoti R Misra.

  YAP/TAZ are transcriptional coactivators that function as the key downstream effectors of Hippo signaling. They are commonly misregulated in most human cancers, which exhibit a higher level of expression and nuclear localization of YAP/TAZ, and display addiction to YAP-dependent transcription. In the nucleus, these coactivators associate with TEA domain transcription factors (TEAD1-4) to regulate the expression of genes that promote cell proliferation and inhibit cell death. Together, this results in an excessive growth of the cancerous tissue. Further, YAP/TAZ play a critical role in tumor metastasis and chemotherapy resistance by promoting cancer stem cell fate. Furthermore, they affect tumor immunity by promoting the expression of PD-L1. Thus, YAP plays an important role in multiple aspects of cancer biology and thus, provides a critical target for cancer therapy. Here we discuss various assays that are used for conducting high-throughput screens of small molecule libraries for hit identification, and subsequent hit validation for successful discovery of potent inhibitors of YAP-transcriptional activity. Furthermore, we describe the advantages and limitations of these assays.

Keywords:  Hippo signaling; cancer; drug discovery; high throughput screening

DOI:  https://doi.org/10.3390/cancers14041029
Semin Cancer Biol. 2022 Feb 18. pii: S1044-579X(22)00045-1. [Epub ahead of print]

Targeting the epigenetic processes to enhance antitumor immunity in small cell lung cancer.

Hao Luo, Jinlu Shan, Hong Zhang, Guanbin Song, Qing Li, Cheng-Xiong Xu.

  Dysregulation of the epigenetic processes, such as DNA methylation, histone modifications, and modulation of chromatin states, drives aberrant transcription that promotes initiation and progression of small cell lung cancer (SCLC). Accumulating evidence has proven crucial roles of epigenetic machinery in modulating immune cell functions and antitumor immune response. Epigenetics-targeting drugs such as DNA methyltransferase inhibitors, histone deacetylase inhibitors, and histone methyltransferase inhibitors involved in preclinical and clinical trials may trigger antitumor immunity. Herein, we summarize the impact of epigenetic processes on tumor immunogenicity and antitumor immune cell functions in SCLC. Furthermore, we review current clinical trials of epigenetic therapy against SCLC and the mechanisms of epigenetic inhibitors to boost antitumor immunity. Eventually, we discuss the opportunities of developing therapeutic regimens combining epigenetic agents with immunotherapy for SCLC.

Keywords:  DNA methylation; Epigenetics; Histone modification; Immunotherapy; Small cell lung cancer

DOI:  https://doi.org/10.1016/j.semcancer.2022.02.018
Commun Biol. 2022 02 23. 5(1): 159

H3K27ac nucleosomes facilitate HMGN localization at regulatory sites to modulate chromatin binding of transcription factors.

Shaofei Zhang, Yuri Postnikov, Alexei Lobanov, Takashi Furusawa, Tao Deng, Michael Bustin.

Nucleosomes containing acetylated H3K27 are a major epigenetic mark of active chromatin and identify cell-type specific chromatin regulatory regions which serve as binding sites for transcription factors. Here we show that the ubiquitous nucleosome binding proteins HMGN1 and HMGN2 bind preferentially to H3K27ac nucleosomes at cell-type specific chromatin regulatory regions. HMGNs bind directly to the acetylated nucleosome; the H3K27ac residue and linker DNA facilitate the preferential binding of HMGNs to the modified nucleosomes. Loss of HMGNs increases the levels of H3K27me3 and the histone H1 occupancy at enhancers and promoters and alters the interaction of transcription factors with chromatin. These experiments indicate that the H3K27ac epigenetic mark enhances the interaction of architectural protein with chromatin regulatory sites and identify determinants that facilitate the localization of HMGN proteins at regulatory sites to modulate cell-type specific gene expression.

DOI: https://doi.org/10.1038/s42003-022-03099-0
Front Cell Dev Biol. 2021 ;9 790129

The Diverse Roles of Histone Demethylase KDM4B in Normal and Cancer Development and Progression.

Zhongze Wang, Huarui Cai, Erhu Zhao, Hongjuan Cui.

  Histone methylation status is an important process associated with cell growth, survival, differentiation and gene expression in human diseases. As a member of the KDM4 family, KDM4B specifically targets H1.4K26, H3K9, H3K36, and H4K20, which affects both histone methylation and gene expression. Therefore, KDM4B is often regarded as a key intermediate protein in cellular pathways that plays an important role in growth and development as well as organ differentiation. However, KDM4B is broadly defined as an oncoprotein that plays key roles in processes related to tumorigenesis, including cell proliferation, cell survival, metastasis and so on. In this review, we discuss the diverse roles of KDM4B in contributing to cancer progression and normal developmental processes. Furthermore, we focus on recent studies highlighting the oncogenic functions of KDM4B in various kinds of cancers, which may be a novel therapeutic target for cancer treatment. We also provide a relatively complete report of the progress of research related to KDM4B inhibitors and discuss their potential as therapeutic agents for overcoming cancer.

Keywords:  KDM4 inhibitor; KDM4B; cancer treatment; histone demethylase; therapeutic target

DOI:  https://doi.org/10.3389/fcell.2021.790129
Noncoding RNA. 2022 Feb 08. pii: 18. [Epub ahead of print]8(1):

HiMoRNA: A Comprehensive Database of Human lncRNAs Involved in Genome-Wide Epigenetic Regulation.

Evgeny Mazurov, Alexey Sizykh, Yulia A Medvedeva.

  Long non-coding RNAs (lncRNAs) play an important role in genome regulation. Specifically, many lncRNAs interact with chromatin, recruit epigenetic complexes and in this way affect large-scale gene expression programs. However, the experimental data about lncRNA-chromatin interactions is still limited. The majority of experimental protocols do not provide any insight into the mechanics of lncRNA-based genome-wide epigenetic regulation. Here we present the HiMoRNA (Histone-Modifying RNA) database, a resource containing correlated lncRNA-epigenetic changes in specific genomic locations genome-wide. HiMoRNA integrates a large amount of multi-omics data to characterize the effects of lncRNA on epigenetic modifications and gene expression. The current release of HiMoRNA includes more than five million associations in humans for ten histone modifications in multiple genomic loci and 4145 lncRNAs. HiMoRNA provides a user-friendly interface to facilitate browsing, searching and retrieving of lncRNAs associated with epigenetic profiles of various chromatin loci. Analysis of the HiMoRNA data suggests that several lncRNA including JPX might be involved not only in regulation of XIST locus but also in direct establishment or maintenance of X-chromosome inactivation. We believe that HiMoRNA is a convenient and valuable resource that can provide valuable biological insights and greatly facilitate functional annotation of lncRNAs.

Keywords:  X inactivation; database; histone modification; lncRNA

DOI:  https://doi.org/10.3390/ncrna8010018
Cancers (Basel). 2022 Feb 18. pii: 1049. [Epub ahead of print]14(4):

Matrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors.

Seiichiro Ishihara, Hisashi Haga.

  Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger mechanotransduction, the conversion of mechanical cues such as stiffness of the matrix to biochemical signaling in the cells, and as a result determine the cellular phenotypes of cancer and stromal cells in tumors. Transcription factors are key molecules for these processes, as they respond to matrix stiffness and are crucial for cellular behaviors. The Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is one of the most studied transcription factors that is regulated by matrix stiffness. The YAP/TAZ are activated by a stiff matrix and promotes malignant phenotypes in cancer and stromal cells, including cancer-associated fibroblasts. In addition, other transcription factors such as β-catenin and nuclear factor kappa B (NF-κB) also play key roles in mechanotransduction in cancer tissues. In this review, the mechanisms of stiffening cancer tissues are introduced, and the transcription factors regulated by matrix stiffness in cancer and stromal cells and their roles in cancer progression are shown.

Keywords:  YAP/TAZ; cancer; cancer associated fibroblasts; collagen; contraction; crosslinking; extracellular matrix; mechanotransduction; stiffness; transcription factors

DOI:  https://doi.org/10.3390/cancers14041049
Discov Oncol. 2021 Nov 24. 12(1): 54

O-GlcNAcylation links oncogenic signals and cancer epigenetics.

Lidong Sun, Suli Lv, Tanjing Song.

  Prevalent dysregulation of epigenetic modifications plays a pivotal role in cancer. Targeting epigenetic abnormality is a new strategy for cancer therapy. Understanding how conventional oncogenic factors cause epigenetic abnormality is of great basic and translational value. O-GlcNAcylation is a protein modification which affects physiology and pathophysiology. In mammals, O-GlcNAcylation is catalyzed by one single enzyme OGT and removed by one single enzyme OGA. O-GlcNAcylation is affected by the availability of the donor, UDP-GlcNAc, generated by the serial enzymatic reactions in the hexoamine biogenesis pathway (HBP). O-GlcNAcylation regulates a wide spectrum of substrates including many proteins involved in epigenetic modification. Like epigenetic modifications, abnormality of O-GlcNAcylation is also common in cancer. Studies have revealed substantial impact on HBP enzymes and OGT/OGA by oncogenic signals. In this review, we will first summarize how oncogenic signals regulate HBP enzymes, OGT and OGA in cancer. We will then integrate this knowledge with the up to date understanding how O-GlcNAcylation regulates epigenetic machinery. With this, we propose a signal axis from oncogenic signals through O-GlcNAcylation dysregulation to epigenetic abnormality in cancer. Further elucidation of this axis will not only advance our understanding of cancer biology but also provide new revenues towards cancer therapy.

Keywords:  Chromatin; Epigenetics; Hexoamine biosynthesis pathway; Histone; O-GlcNAcylation; OGA; OGT

DOI:  https://doi.org/10.1007/s12672-021-00450-5
J Hepatocell Carcinoma. 2022 ;9 99-112

Current Perspectives on the Unique Roles of Exosomes in Drug Resistance of Hepatocellular Carcinoma.

Dongdong Xue, Jingzhao Han, Ze Liang, Lin Jia, Yifan Liu, Hongfang Tuo, Yanhui Peng.

  As a common malignant tumor worldwide, the prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory, even though treatment methods have improved. Despite the developments in traditional chemotherapy and emerging targeted immunotherapy, the problem of recurrence and metastasis of HCC and adverse effects on survival and prognosis are still serious. Drug resistance is a daunting challenge that impedes HCC treatment. Exosomes, a class of extracellular vesicles ranging in size from 30 to 100 nm, have been the focus of recent studies. Exosomes can activate various signaling pathways and regulate the tumor microenvironment with their cargo, which includes functional lipids, proteins, and nucleic acids. Thus, they change the phenotype of recipient cells via exosome-mediated communication. Exosomes secreted by tumors or stromal cells can also transfer drug-resistant traits to other tumor cells. However, their effects on drug resistance in HCC are not completely understood. In this review, we summarize and discuss the underlying relationship between exosomes and drug resistance in HCC. In addition, we also show that exosomes may act as candidate biomarkers for predicting and monitoring drug responses and as potential targets or vectors to reverse the drug resistance of HCC.

Keywords:  exosome; hepatocellular carcinoma; targeted therapy; tumor microenvironment

DOI:  https://doi.org/10.2147/JHC.S351038
Cancer Control. 2022 Jan-Dec;29:29 10732748221078160

Epigenetic Inheritance From Normal Origin Cells Can Determine the Aggressive Biology of Tumor-Initiating Cells and Tumor Heterogeneity.

Jiliang Feng, Dawei Zhao, Fudong Lv, Zhongyu Yuan.

  The acquisition of genetic- and epigenetic-abnormalities during transformation has been recognized as the two fundamental factors that lead to tumorigenesis and determine the aggressive biology of tumor cells. However, there is a regularity that tumors derived from less-differentiated normal origin cells (NOCs) usually have a higher risk of vascular involvement, lymphatic and distant metastasis, which can be observed in both lymphohematopoietic malignancies and somatic cancers. Obviously, the hypothesis of genetic- and epigenetic-abnormalities is not sufficient to explain how the linear relationship between the cellular origin and the biological behavior of tumors is formed, because the cell origin of tumor is an independent factor related to tumor biology. In a given system, tumors can originate from multiple cell types, and tumor-initiating cells (TICs) can be mapped to different differentiation hierarchies of normal stem cells, suggesting that the heterogeneity of the origin of TICs is not completely chaotic. TIC's epigenome includes not only genetic- and epigenetic-abnormalities, but also established epigenetic status of genes inherited from NOCs. In reviewing previous studies, we found much evidence supporting that the status of many tumor-related "epigenetic abnormalities" in TICs is consistent with that of the corresponding NOC of the same differentiation hierarchy, suggesting that they may not be true epigenetic abnormalities. So, we speculate that the established statuses of genes that control NOC's migration, adhesion and colonization capabilities, cell-cycle quiescence, expression of drug transporters, induction of mesenchymal formation, overexpression of telomerase, and preference for glycolysis can be inherited to TICs through epigenetic memory and be manifested as their aggressive biology. TICs of different origins can maintain different degrees of innate stemness from NOC, which may explain why malignancies with stem cell phenotypes are usually more aggressive.

Keywords:  epigenetic abnormality; heterogeneity; tumor stem cell; tumor-initiating cell; tumorigenesis

DOI:  https://doi.org/10.1177/10732748221078160
Biochem Soc Trans. 2022 Feb 22. pii: BST20210863. [Epub ahead of print]

Computational exploration of cellular communication in skin from emerging single-cell and spatial transcriptomic data.

Suoqin Jin, Raul Ramos.

  Tissue development and homeostasis require coordinated cell-cell communication. Recent advances in single-cell sequencing technologies have emerged as a revolutionary method to reveal cellular heterogeneity with unprecedented resolution. This offers a great opportunity to explore cell-cell communication in tissues systematically and comprehensively, and to further identify signaling mechanisms driving cell fate decisions and shaping tissue phenotypes. Using gene expression information from single-cell transcriptomics, several computational tools have been developed for inferring cell-cell communication, greatly facilitating analysis and interpretation. However, in single-cell transcriptomics, spatial information of cells is inherently lost. Given that most cell signaling events occur within a limited distance in tissues, incorporating spatial information into cell-cell communication analysis is critical for understanding tissue organization and function. Spatial transcriptomics provides spatial location of cell subsets along with their gene expression, leading to new directions for leveraging spatial information to develop computational approaches for cell-cell communication inference and analysis. These computational approaches have been successfully applied to uncover previously unrecognized mechanisms of intercellular communication within various contexts and across organ systems, including the skin, a formidable model to study mechanisms of cell-cell communication due to the complex interactions between the different cell populations that comprise it. Here, we review emergent cell-cell communication inference tools using single-cell transcriptomics and spatial transcriptomics, and highlight the biological insights gained by applying these computational tools to exploring cellular communication in skin development, homeostasis, disease and aging, as well as discuss future potential research avenues.

Keywords:  cell–cell communication; computational tools; single-cell genomics; skin biology; spatial transcriptomics

DOI:  https://doi.org/10.1042/BST20210863
Biomedicines. 2022 Feb 03. pii: 374. [Epub ahead of print]10(2):

HDAC9 Contributes to Serous Ovarian Cancer Progression through Regulating Epithelial-Mesenchymal Transition.

Long Xu, Jian Wang, Buhan Liu, Jiaying Fu, Yuanxin Zhao, Sihang Yu, Luyan Shen, Xiaoyu Yan, Jing Su.

  Epithelial ovarian cancer has the highest mortality rate of all gynecological malignant tumors. Metastasis is the main cause of poor prognosis in patients with ovarian cancer. Epigenetic and protein post-translational modifications play important roles in tumor metastasis. As a member of class IIa histone deacetylases, histone deacetylase 9 (HDAC9) is involved in many biological processes by deacetylating histone and nonhistone proteins. However, its roles in ovarian cancer remain unclear. In this study, we found that patients with serous ovarian cancer with high expression of HDAC9 had poor prognoses. On the contrary, patients with non-serous ovarian cancer with high expression of HDAC9 had higher survival rates. In serous ovarian cancer, overexpressed HDAC9 may promote cell migration through the forkhead box protein O1 (FOXO1)/transforming growth factor-beta (TGF-β) axis. In non-serous ovarian cancer, overexpressed HDAC9 exerts antitumor effects that might be caused by the suppression of β-catenin signaling. Therefore, HDAC9 may be a potential target for individualized treatment of patients with different histological subtypes of ovarian cancer.

Keywords:  FOXO1; HDAC9; TGF-β; epithelial ovarian cancer; epithelial–mesenchymal transition; β-catenin

DOI:  https://doi.org/10.3390/biomedicines10020374
Epigenetics Chromatin. 2022 Feb 22. 15(1): 7

Evolutionary adaptation of the Polycomb repressive complex 2.

Sabrina Fischer, Lisa Marie Weber, Robert Liefke.

  The Polycomb repressive complex 2 (PRC2) is an essential chromatin regulatory complex involved in repressing the transcription of diverse developmental genes. PRC2 consists of a core complex; possessing H3K27 methyltransferase activity and various associated factors that are important to modulate its function. During evolution, the composition of PRC2 and the functionality of PRC2 components have changed considerably. Here, we compare the PRC2 complex members of Drosophila and mammals and describe their adaptation to altered biological needs. We also highlight how the PRC2.1 subcomplex has gained multiple novel functions and discuss the implications of these changes for the function of PRC2 in chromatin regulation.

Keywords:  Chromatin; CpG Islands; Drosophila; EPOP; EZHIP; Evolution; JARID2; PALI1; PRC2; Polycomb

DOI:  https://doi.org/10.1186/s13072-022-00439-6
Neoplasma. 2022 Feb 22. pii: 210726N1046. [Epub ahead of print]

Tumor suppressive lncRNA MEG3 binds to EZH2 and enhances CXCL3 methylation in gallbladder cancer.

De-Qiang Li, Yi-Ren Ding, Jin-Hui Che, Zhan Su, Wei-Zhong Yang, Lu Xu, Yun-Jiu Li, Hai-Hong Wang, Wu-Yuan Zhou.

Gallbladder cancer is a malignant tumor with a high mortality rate. Accumulating evidence supports that lncRNA MEG3 may halt the progression of gallbladder cancer, while the downstream mechanism is rarely studied. Thus, we aim to investigate the molecular basis of the tumor-suppressing role of lncRNA MEG3 in gallbladder cancer. The expression of lncRNA MEG3 and CXCL3 was measured in patient serum and cell lines of gallbladder cancer. The viability, apoptosis, migration, and invasion of gallbladder cancer cells were assessed following ectopic MEG3 expression, as detected by CCK-8, flow cytometry, and Transwell assays. The interaction among lncRNA MEG3, EZH2, and CXCL3 was explored through ChIP, RNA pull-down, and RIP assays. The effects of lncRNA MEG3 and CXCL3 on tumor growth were evaluated by a mouse xenograft model. LncRNA MEG3 was expressed at a low level in gallbladder cancer patient serum and cell lines, while CXCL3 was highly expressed. MEG3 overexpression repressed the malignant behaviors of gallbladder cancer cells and promoted their apoptosis. MEG3 was mainly localized in the nucleus. MEG3 bound to EZH2, and EZH2 catalyzed the H3K27 trimethylation of the CXCL3 promoter region. MEG3 downregulated CXCL3 by activating EZH2-mediated H3K27 trimethylation of CXCL3; MEG3 overexpression attenuated cancer cell malignant behaviors in vitro and suppressed tumor growth in vivo in gallbladder cancer by inhibiting CXCL3 expression. Altogether, our results indicate that lncRNA MEG3 impedes gallbladder cancer development via the EZH2-CXCL3 axis, offering potential biomarkers for gallbladder cancer management.

DOI: https://doi.org/10.4149/neo_2022_210726N1046
Pharmaceutics. 2022 Feb 10. pii: 391. [Epub ahead of print]14(2):

Identification of a Quinone Derivative as a YAP/TEAD Activity Modulator from a Repurposing Library.

Angela Lauriola, Elisa Uliassi, Matteo Santucci, Maria Laura Bolognesi, Marco Mor, Laura Scalvini, Gian Marco Elisi, Gaia Gozzi, Lorenzo Tagliazucchi, Gaetano Marverti, Stefania Ferrari, Lorena Losi, Domenico D'Arca, Maria Paola Costi.

  The transcriptional regulators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) are the major downstream effectors in the Hippo pathway and are involved in cancer progression through modulation of the activity of TEAD (transcriptional enhanced associate domain) transcription factors. To exploit the advantages of drug repurposing in the search of new drugs, we developed a similar approach for the identification of new hits interfering with TEAD target gene expression. In our study, a 27-member in-house library was assembled, characterized, and screened for its cancer cell growth inhibition effect. In a secondary luciferase-based assay, only seven compounds confirmed their specific involvement in TEAD activity. IA5 bearing a p-quinoid structure reduced the cytoplasmic level of phosphorylated YAP and the YAP-TEAD complex transcriptional activity and reduced cancer cell growth. IA5 is a promising hit compound for TEAD activity modulator development.

Keywords:  TEAD transcription factor; chemoinformatic; leads repurposing; luciferase assay; p-quinoid derivatives

DOI:  https://doi.org/10.3390/pharmaceutics14020391
RNA. 2022 Feb 24. pii: rna.079129.122. [Epub ahead of print]

Vault RNA1-1 riboregulates the autophagic function of p62 by binding to K7/R21 that are critical for p62 oligomerisation.

Magdalena Büscher, Rastislav Horos, Ina Huppertz, Kevin Haubrich, Nikolay Dobrev, Florence Baudin, Janosch Hennig, Matthias W Hentze.

  Cellular processes can be regulated at multiple levels, including transcriptional, post-transcriptional and post-translational mechanisms. We have recently shown that the small, non-coding vault RNA1-1 negatively riboregulates p62 oligomerisation in selective autophagy through direct interaction with the autophagic receptor. This function is highly specific for this Pol III transcript, but the determinants of this specificity and a mechanistic explanation of how vault RNA1-1 inhibits p62 oligomerisation are lacking. Here, we combine biochemical and functional experiments to answer these questions. We show that the PB1 domain and adjacent linker region of p62 (aa 1-122) are necessary and sufficient for specific vault RNA1-1 binding, and identify lysine 7 and arginine 21 as key hinges for p62 riboregulation. Chemical structure probing of vault RNA1-1 further reveals a central flexible loop within vault RNA1-1 that is required for the specific interaction with p62. Overall, our data provide molecular insight into how a small RNA riboregulates protein-protein interactions critical to the activation of specific autophagy.

Keywords:  autophagy; p62; riboregulation; small ncRNA; vault RNA

DOI:  https://doi.org/10.1261/rna.079129.122
Discov Oncol. 2021 Jul 01. 12(1): 20

Diaphanous related formin 3 knockdown suppresses cell proliferation and metastasis of osteosarcoma cells.

Zehua Zhang, Fei Dai, Fei Luo, Wenjie Wu, Shuai Zhang, Rui Zhou, Jianzhong Xu, Qiang Zhou, Lei Song.

  Osteosarcoma is a malignant osteoblastic tumor that can gravely endanger the lives and health of children and adolescents. Therefore, there is an urgent need to explore new biomarkers for osteosarcoma and determine new targeted therapies to improve the efficacy of osteosarcoma treatment. Diaphanous related formin 3 (DIAPH3) promotes tumorigenesis in hepatocellular carcinoma and lung adenocarcinoma, suggesting that DIAPH3 may be a target for tumor therapy. To date, there have been no reports on the function of DIAPH3 in osteosarcoma. DIAPH3 protein expression in osteosarcoma tissues and healthy bone tissues adjacent to cancer cells was examined by immunohistochemical staining. DIAPH3 mRNA expression correlates with overall survival and reduced disease-free survival. DIAPH3 protein is upregulated in osteosarcoma tissues, and its expression is significantly associated with tumor size, tumor stage, node metastasis, and distant metastasis. Functional in vitro experiments revealed that DIAPH3 knockdown suppressed cell proliferation and suppressed cell migration and invasion of osteosarcoma cell lines MG-63 and HOS. Functional experiments demonstrated that DIAPH3 knockdown inhibited subcutaneous tumor growth and lung metastasis in vivo. In conclusion, DIAPH3 expression can predict the clinical outcome of osteosarcoma. In addition, DIAPH3 is involved in the proliferation and metastasis of osteosarcoma, and as such, DIAPH3 may be a potential therapeutic target for osteosarcoma.

Keywords:  Diaphanous related formin 3; In vitro; In vivo; Oncogenic role; Osteosarcoma; Potential therapeutic target

DOI:  https://doi.org/10.1007/s12672-021-00415-8
Comb Chem High Throughput Screen. 2022 Feb 21.

Pan-cancer analysis of histone methyltransferase KMT2D with potential implications for prognosis and immunotherapy in human cancer.

Guoning Chen, Peijie Chen, Jianwen Zhou, Guangcheng Luo.

  BACKGROUND: Pan-cancer analysis is an efficient tool to obtain a panoramic view of cancer-related genes and identify their oncogenic processes, facilitating the development of new therapeutic targets. lysine methyltransferase 2D (KMT2D), acting as a major enhancer coactivator for mammalian cells, is one of the most frequently mutated genes across various cancer types and is considered an oncogene and a rationale for epigenetic therapeutic targets.OBJECTIVE: This study was designed to explore the potential role of KMT2D in human cancer through a pan-cancer analysis Methods: The expression of KMT2D was assessed in normal tissues and cell lines, and pan-cancers from The Cancer Genome Atlas (TCGA), Cancer Cell Line Encyclopedia (CCLE), and Genotype-Tissue Expression (GTE) datasets were used to explore its correlation with prognosis, immune cell infiltration, tumor mutation burden, microsatellite instability, and mismatch repair.
RESULTS: KMT2D expression was heterogeneous across different cancer types. Increased KMT2D indicated a worse prognosis in adrenocortical carcinoma (ACC), brain lower-grade glioma (LGG), and mesothelioma (MESO), while patients with high KMT2D expression showed better outcomes in renal clear cell carcinoma (KIRC). Moreover, KMT2D expression was positively correlated with immune cell infiltration and negative tumor mutation burden in multiple cancers. In addition, a significant correlation between KMT2D and immune checkpoint-related genes or mismatch repair genes was identified.
CONCLUSIONS: These findings support the hypothesis that KMT2D is not only a potential biomarker for prognosis and immunotherapy response prediction, but also an essential immune regulator in human cancer.

Keywords:  Immunotherapy; KMT2D; Overall survival; Pan-cancer Analysis; Prognosis

DOI:  https://doi.org/10.2174/1386207325666220221092318
Mol Biol Cell. 2022 Feb 23. mbcE20080523

The methyltransferase enzymes, KMT2D, SETD1B, and ASH1L, are key mediators of both metabolic and epigenetic changes during cellular senescence.

Timothy Nacarelli, Ashley Azar, Manali Potnis, Gregg Johannes, Joshua Mell, F Brad Johnson, Holly Brown-Borg, Eishi Nogouchi, Christian Sell.

Cellular senescence is a terminal cell fate characterized by growth arrest, and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction and rapamycin. This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence, but continued to divide at a slow rate even at high passage, in contrast to either rapamycin treatment or methionine restriction, both of which extended lifespan but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism, including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.

DOI: https://doi.org/10.1091/mbc.E20-08-0523
Biomolecules. 2022 Jan 29. pii: 229. [Epub ahead of print]12(2):

Localized Proteasomal Degradation: From the Nucleus to Cell Periphery.

Xing Guo.

  The proteasome is responsible for selective degradation of most cellular proteins. Abundantly present in the cell, proteasomes not only diffuse in the cytoplasm and the nucleus but also associate with the chromatin, cytoskeleton, various membranes and membraneless organelles/condensates. How and why the proteasome gets to these specific subcellular compartments remains poorly understood, although increasing evidence supports the hypothesis that intracellular localization may have profound impacts on the activity, substrate accessibility and stability/integrity of the proteasome. In this short review, I summarize recent advances on the functions, regulations and targeting mechanisms of proteasomes, especially those localized to the nuclear condensates and membrane structures of the cell, and I discuss the biological significance thereof in mediating compartmentalized protein degradation.

Keywords:  condensate; membrane; myristoylation; nucleus; proteasome; ubiquitination

DOI:  https://doi.org/10.3390/biom12020229
Int J Oncol. 2022 Apr;pii: 38. [Epub ahead of print]60(4):

circ‑LRP6 contributes to osteosarcoma progression by regulating the miR‑141‑3p/HDAC4/HMGB1 axis.

Yali Yu, Guixiang Dong, Zijun Li, Yan Zheng, Zhisong Shi, Guanghui Wang.

  Circular RNA‑lipoprotein receptor 6 (circ‑LRP6) serves a role in promoting the tumorigenesis of retinoblastoma, esophageal squamous cell cancer and oral squamous cell carcinoma; however, whether circ‑LRP6 demonstrates the same effect in osteosarcoma (OS) is yet to be fully elucidated. The present study aimed to analyze the expression, role and potential molecular mechanism of circ‑LRP6 in OS. The expression levels of circ‑LRP6, microRNA (miR)‑141‑3p, histone deacetylase 4 (HDAC4) and high mobility group protein 1 (HMGB1) were evaluated by reverse transcription-quantitative PCR in OS tissues and cell lines. Cell Counting Kit‑8, Transwell and Matrigel assays were conducted to evaluate cell proliferation, migration and invasion, respectively. Western blotting was also performed to determine HDAC4 and HMGB1 protein expression levels. Bioinformatics and dual‑luciferase reporter assays were used to predict and analyze the interactions between circ‑LRP6 and miR‑141‑3p, miR‑141‑3p and HDAC4, as well as between miR‑141‑3p and HMGB1. Additionally, RNA immunoprecipitation was performed to verify the association between circ‑LRP6 and miR‑141‑3p. The results confirmed that circ‑LRP6 was highly expressed in OS tissues and cell lines. In addition, circ‑LRP6 negatively regulated the expression of miR‑141‑3p and, in turn, miR‑141‑3p negatively regulated HDAC4 and HMGB1 expression. Functional assays revealed that circ‑LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells, whereas the inhibition of miR‑141‑3p or the overexpression of either HDAC4 or HMGB1 partly reversed the inhibitory effect of circ‑LRP6 knockdown. In summary, the present study determined that circ‑LRP6 knockdown inhibited the proliferation, migration and invasion of OS cells by regulating the miR‑141‑3p/HDAC4/HMGB1 axis.

Keywords:  circular RNA‑lipoprotein receptor 6; high mobility group protein 1; histone deacetylase 4; microRNA-141‑3p; osteosarcoma

DOI:  https://doi.org/10.3892/ijo.2022.5328
Front Cell Dev Biol. 2022 ;10 780176

The Histone H3K27me3 Demethylases KDM6A/B Resist Anoikis and Transcriptionally Regulate Stemness-Related Genes.

Mohammed Razeeth Shait Mohammed, Mazin Zamzami, Hani Choudhry, Firoz Ahmed, Bushra Ateeq, Mohammad Imran Khan.

  Epithelial cancer cells that lose attachment from the extracellular matrix (ECM) to seed in a distant organ often undergo anoikis's specialized form of apoptosis. Recently, KDM3A (H3K9 demethylase) has been identified as a critical effector of anoikis in cancer cells. However, whether other histone demethylases are involved in promoting or resisting anoikis remains elusive. We screened the major histone demethylases and found that both H3K27 histone demethylases, namely, KDM6A/B were highly expressed during ECM detachment. Inhibition of the KDM6A/B activity by using a specific inhibitor results in reduced sphere formation capacity and increased apoptosis. Knockout of KDM6B leads to the loss of stem cell properties in solitary cells. Furthermore, we found that KDM6B maintains stemness by transcriptionally regulating the expression of stemness genes SOX2, SOX9, and CD44 in detached cells. KDM6B occupies the promoter region of both SOX2 and CD44 to regulate their expression epigenetically. We also noticed an increased occupancy of the HIF1α promoter by KDM6B, suggesting its regulatory role in maintaining hypoxia in detached cancer cells. This observation was further strengthened as we found a significant positive association in the expression of both KDM6B and HIF1α in various cancer types. Overall, our results reveal a novel transcriptional program that regulates resistance against anoikis and maintains stemness-like properties.

Keywords:  CD44; HIF1α; SOX2; anoikis; histone demethylases

DOI:  https://doi.org/10.3389/fcell.2022.780176
Biomolecules. 2022 Feb 18. pii: 327. [Epub ahead of print]12(2):

Regulation of p53 Function by Formation of Non-Nuclear Heterologous Protein Complexes.

Lev Zavileyskiy, Victoria Bunik.

  A transcription factor p53 is activated upon cellular exposure to endogenous and exogenous stresses, triggering either homeostatic correction or cell death. Depending on the stress level, often measurable as DNA damage, the dual outcome is supported by p53 binding to a number of regulatory and metabolic proteins. Apart from the nucleus, p53 localizes to mitochondria, endoplasmic reticulum and cytosol. We consider non-nuclear heterologous protein complexes of p53, their structural determinants, regulatory post-translational modifications and the role in intricate p53 functions. The p53 heterologous complexes regulate the folding, trafficking and/or action of interacting partners in cellular compartments. Some of them mainly sequester p53 (HSP proteins, G6PD, LONP1) or its partners (RRM2B, PRKN) in specific locations. Formation of other complexes (with ATP2A2, ATP5PO, BAX, BCL2L1, CHCHD4, PPIF, POLG, SOD2, SSBP1, TFAM) depends on p53 upregulation according to the stress level. The p53 complexes with SIRT2, MUL1, USP7, TXN, PIN1 and PPIF control regulation of p53 function through post-translational modifications, such as lysine acetylation or ubiquitination, cysteine/cystine redox transformation and peptidyl-prolyl cis-trans isomerization. Redox sensitivity of p53 functions is supported by (i) thioredoxin-dependent reduction of p53 disulfides, (ii) inhibition of the thioredoxin-dependent deoxyribonucleotide synthesis by p53 binding to RRM2B and (iii) changed intracellular distribution of p53 through its oxidation by CHCHD4 in the mitochondrial intermembrane space. Increasing knowledge on the structure, function and (patho)physiological significance of the p53 heterologous complexes will enable a fine tuning of the settings-dependent p53 programs, using small molecule regulators of specific protein-protein interactions of p53.

Keywords:  heterologous non-nuclear complexes of p53; intracellular localization of p53; p53 sequestration; p53 trafficking; thiol/disulfide-dependent regulation of p53 functions

DOI:  https://doi.org/10.3390/biom12020327
Cancers (Basel). 2022 Feb 11. pii: 894. [Epub ahead of print]14(4):

Activation of ABCC Genes by Cisplatin Depends on the CoREST Occurrence at Their Promoters in A549 and MDA-MB-231 Cell Lines.

Maciej Sobczak, Magdalena Strachowska, Karolina Gronkowska, Agnieszka Robaszkiewicz.

  Although cisplatin-based therapies are common among anticancer approaches, they are often associated with the development of cancer drug resistance. This phenomenon is, among others, caused by the overexpression of ATP-binding cassette, membrane-anchored transporters (ABC proteins), which utilize ATP to remove, e.g., chemotherapeutics from intracellular compartments. To test the possible molecular basis of increased expression of ABCC subfamily members in a cisplatin therapy mimicking model, we generated two cisplatin-resistant cell lines derived from non-small cell lung cancer cells (A549) and triple-negative breast cancer cells (MDA-MB-231). Analysis of data for A549 cells deposited in UCSC Genome Browser provided evidence on the negative interdependence between the occurrence of the CoREST complex at the gene promoters and the overexpression of ABCC genes in cisplatin-resistant lung cancer cells. Pharmacological inhibition of CoREST enzymatic subunits-LSD1 and HDACs-restored gene responsiveness to cisplatin. Overexpression of CoREST-free ABCC10 in cisplatin-resistant phenotypes was caused by the activity of EP300 that was enriched at the ABCC10 promoter in drug-treated cells. Cisplatin-induced and EP300-dependent transcriptional activation of ABCC10 was only possible in the presence of p53. In summary, the CoREST complex prevents the overexpression of some multidrug resistance proteins from the ABCC subfamily in cancer cells exposed to cisplatin. p53-mediated activation of some ABCC genes by EP300 occurs once their promoters are devoid of the CoREST complex.

Keywords:  ABC-family transporters; CoREST; EP300; multidrug-resistance; p53

DOI:  https://doi.org/10.3390/cancers14040894
Front Cell Dev Biol. 2021 ;9 826248

Biogenesis and Breakdown of Lipid Droplets in Pathological Conditions.

Claudio M Fader Kaiser, Patricia S Romano, M Cristina Vanrell, Cristian A Pocognoni, Julieta Jacob, Benjamín Caruso, Laura R Delgui.

  Lipid droplets (LD) have long been considered as mere fat drops; however, LD have lately been revealed to be ubiquitous, dynamic and to be present in diverse organelles in which they have a wide range of key functions. Although incompletely understood, the biogenesis of eukaryotic LD initiates with the synthesis of neutral lipids (NL) by enzymes located in the endoplasmic reticulum (ER). The accumulation of NL leads to their segregation into nanometric nuclei which then grow into lenses between the ER leaflets as they are further filled with NL. The lipid composition and interfacial tensions of both ER and the lenses modulate their shape which, together with specific ER proteins, determine the proneness of LD to bud from the ER toward the cytoplasm. The most important function of LD is the buffering of energy. But far beyond this, LD are actively integrated into physiological processes, such as lipid metabolism, control of protein homeostasis, sequestration of toxic lipid metabolic intermediates, protection from stress, and proliferation of tumours. Besides, LD may serve as platforms for pathogen replication and defense. To accomplish these functions, from biogenesis to breakdown, eukaryotic LD have developed mechanisms to travel within the cytoplasm and to establish contact with other organelles. When nutrient deprivation occurs, LD undergo breakdown (lipolysis), which begins with the LD-associated members of the perilipins family PLIN2 and PLIN3 chaperone-mediated autophagy degradation (CMA), a specific type of autophagy that selectively degrades a subset of cytosolic proteins in lysosomes. Indeed, PLINs CMA degradation is a prerequisite for further true lipolysis, which occurs via cytosolic lipases or by lysosome luminal lipases when autophagosomes engulf portions of LD and target them to lysosomes. LD play a crucial role in several pathophysiological processes. Increased accumulation of LD in non-adipose cells is commonly observed in numerous infectious diseases caused by intracellular pathogens including viral, bacterial, and parasite infections, and is gradually recognized as a prominent characteristic in a variety of cancers. This review discusses current evidence related to the modulation of LD biogenesis and breakdown caused by intracellular pathogens and cancer.

Keywords:  LD biogenesis; LD breakdown; cancer; lipid droplet (LD); protozoans; viral infection

DOI:  https://doi.org/10.3389/fcell.2021.826248