bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒03‒13
seventeen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Role of autophagy in drug resistance and regulation of osteosarcoma (Review).
  2. A fluorogenic probe targeting two spatially separated enzymes for selective imaging of cancer cells.
  3. Histone variant-specific post-translational modifications.
  4. Identification of Small-molecule YAP-TEAD inhibitors by High-throughput docking for the Treatment of colorectal cancer.
  5. Flow cytometric single cell-based assay to simultaneously detect cell death, cell cycling, DNA content and cell senescence.
  6. Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells.
  7. Targeting the IGF/PI3K/mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer.
  8. Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs.
  9. miR-3189-targeted GLUT3 repression by HDAC2 knockdown inhibits glioblastoma tumorigenesis through regulating glucose metabolism and proliferation.
  10. Focus on the classical and non-classical functions of EZH2: Guide the development of inhibitors and degraders.
  11. Single cell analysis of mechanical properties and EMT-related gene expression profiles in cancer fingers.
  12. Constitutive β-catenin overexpression represses lncRNA MIR100HG transcription via HDAC6-mediated histone modification in colorectal cancer.
  13. Yes-associated protein 1 exerts its tumor-promoting effects and increases cisplatin resistance in tongue squamous cell carcinoma cells by dysregulating Hippo signal pathway.
  14. Epigenetic Regulation: A Link between Inflammation and Carcinogenesis.
  15. Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications.
  16. A narrative review for the Hippo-YAP pathway in cancer survival and immunity: the Yin-Yang dynamics.
  17. HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway.
  1. Mol Clin Oncol. 2022 Mar;16(3): 72
    Role of autophagy in drug resistance and regulation of osteosarcoma (Review).
    Yanchuan Pu, Jin Wang, Shizhong Wang.
      Osteosarcoma (OS) is a malignant tumor originating from primitive mesenchymal tissue that occurs mostly in children and adolescents. It is the most common type of malignant tumor originating from bone. The combination of chemotherapy and surgery is an important treatment strategy for OS; however, multidrug resistance frequently leads to failure of chemotherapy for OS. Autophagy is considered an important mechanism through which bone tumor cells escape apoptosis; inhibition of autophagy may significantly increase the sensitivity of tumor cells to chemotherapeutic drugs. The present review discusses the relationship between chemotherapy resistance and autophagy-related genes, the regulation of autophagy in OS, as well as drugs that inhibit protective autophagy in tumors or cause autophagic death of OS cells or increase their sensitivity to chemotherapy drugs, thereby reducing chemotherapy resistance and increasing efficacy.
    Keywords:  autophagy; drug regulation; drug resistance; osteosarcoma
    DOI:  https://doi.org/10.3892/mco.2022.2505
  2. Chem Commun (Camb). 2022 Mar 10.
    A fluorogenic probe targeting two spatially separated enzymes for selective imaging of cancer cells.
    Sang-Hyun Park, Hyoje Jung, Yujun Kim, Injae Shin.
      We describe a fluorogenic probe BocLys(Ac)-AB-FC targeting both histone deacetylases (HDACs) and cathepsin L, which are overexpressed in spatially separated subcellular organelles of cancer cells. The results show that this fluorogenic probe can be used for selective cancer cell imaging without interference arising from normal cells.
    DOI:  https://doi.org/10.1039/d2cc01082h
  3. Semin Cell Dev Biol. 2022 Mar 09. pii: S1084-9521(22)00051-9. [Epub ahead of print]
    Histone variant-specific post-translational modifications.
    Faith M Joseph, Nicolas L Young.
      Post-translational modifications (PTMs) of histones play a key role in DNA-based processes and contribute to cell differentiation and gene function by adding an extra layer of regulation. Variations in histone sequences within each family of histones expands the chromatin repertoire and provide further mechanisms for regulation and signaling. While variants are known to be present in certain genomic loci and carry out important functions, much remains unknown about variant-specific PTMs and their role in regulating chromatin. This ambiguity is in part due to the limited technologies and appropriate reagents to identify and quantitate variant-specific PTMs. Nonetheless, histone variants are an integral portion of the chromatin system and the understanding of their modifications and resolving how PTMs function differently on specific variants is paramount to the advancement of the field. Here we review the current knowledge on post-translational modifications specific to histone variants, with an emphasis on well-characterized PTMs of known function. While not every possible PTM is addressed, we present key variant-specific PTMs and what is known about their function and mechanisms in convenient reference tables.
    Keywords:  Chromatin; Epigenetics; Histone Variants; Histones; Post-translational modifications; Replication-independent
    DOI:  https://doi.org/10.1016/j.semcdb.2022.02.012
  4. Bioorg Chem. 2022 Feb 26. pii: S0045-2068(22)00112-2. [Epub ahead of print]122 105707
    Identification of Small-molecule YAP-TEAD inhibitors by High-throughput docking for the Treatment of colorectal cancer.
    Lijun Li, Ruizhe Li, Yumei Wang.
      The YAP-TEAD transcriptional complex is responsible for the expression of genes that regulate cancer cell growth, proliferation, and apoptosis. Dysregulation of the Hippo pathway due to overexpression of YAP has been reported in various cancers. Inhibition of TEAD represses the expression of associated genes, proving the value of this transcription factor for the development of novel anti-cancer therapies. We retrieved a promising hit compound L06 which is a potent TEAD4 inhibitor through docking-based virtual screening. L06 inhibits TEAD autopalmitoylation, interrupts YAP-TEAD interaction, and reduces the YAP-TEAD transcriptional activity. Moreover, L06 reduces the expression of CTGF, inhibits HCT 116 colorectal cancer cell proliferation, migration and invasion. The YAP-TEAD complex is a viable drug target, and L06 is a lead compound for the development of more potent TEAD inhibitors to treat colorectal cancer and other hyperproliferative pathologies.
    Keywords:  Anti-migration; Colorectal cancer; High-throughput docking; Inhibitors; YAP-TEAD
    DOI:  https://doi.org/10.1016/j.bioorg.2022.105707
  5. Cell Death Differ. 2022 Mar 09.
    Flow cytometric single cell-based assay to simultaneously detect cell death, cell cycling, DNA content and cell senescence.
    Elizabeth Lieschke, Zilu Wang, Catherine Chang, Clare E Weeden, Gemma L Kelly, Andreas Strasser.
      Cell death, cell cycle arrest and cellular senescence are three distinct cellular responses that can be induced by oncogene activation and diverse anti-cancer agents, and this often requires the action of the tumour suppressor TP53. Within a cell population, or even within an individual cell, these processes are not necessarily mutually exclusive. It is therefore important to measure all these processes simultaneously. However, current assays generally visualise only one or at best two responses, often only detecting the dominant one. Here, we present a novel flow cytometric assay that allows simultaneous assessment of cell viability and cell cycling through measurement of DNA content and DNA synthesis, and markers of cell senescence at the single cell level. We demonstrate that this assay can be performed on both human and murine cells, that are either cancerous or non-transformed, and can help to dissect complex cell fate decisions. We believe that this experimental tool will be useful for the study of diverse biological processes.
    DOI:  https://doi.org/10.1038/s41418-022-00964-7
  6. Front Pharmacol. 2021 ;12 788667
    Sorafenib-Induced Autophagy Promotes Glycolysis by Upregulating the p62/HDAC6/HSP90 Axis in Hepatocellular Carcinoma Cells.
    Xiaoyu Yan, Rui Tian, Jicheng Sun, Yuanxin Zhao, Buhan Liu, Jing Su, Minghua Li, Wei Sun, Xuesong Xu.
      Sorafenib has attracted much attention as the first drug approved by the FDA for the treatment of advanced hepatocellular carcinoma (HCC). Because of the drug tolerance, the overall outcomes were far from satisfactory. Current studies suggest that changes in glucose metabolism induced by sorafenib are the pivotal resistant mechanism of HCC cells, but the specific regulatory mechanism remains unclear, which makes it difficult to increase drug sensitivity by targeting glycolysis. As a metabolic-recycling pathway, autophagy regulates multiple important pathways involved in cell survival and death. In this study, we found the expression of key autophagy proteins were closely related to the prognosis and progression of HCC patients. Based on in vitro experiments, our studies showed sorafenib induced autophagy in HCC cells. Inhibition of autophagy by chloroquine could significantly increase the sensitivity of HCC cells to sorafenib and reverse the enhancement of glycolysis. Furthermore, sorafenib-induced autophagy promoted the deacetylase activity of HDAC6 by degrading p62, which promoted the activity of PKM2 by regulating the acetylation of its critical substrate HSP90. In this study, we investigated the role of autophagy-induced HDAC6 in regulating the key glycolytic enzyme PKM2, which may be helpful to clarify the relationship between autophagy and glycolysis in a sorafenib-resistant mechanism. Targeting p62/HDAC6/HSP90 could herald a potential improvement in HCC therapy.
    Keywords:  HDAC6; autophagy; glycolysis; hepatocellular carcinoma; p62; sorafenib
    DOI:  https://doi.org/10.3389/fphar.2021.788667
  7. J Bone Oncol. 2022 Apr;33 100419
    Targeting the IGF/PI3K/mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer.
    Danh D Truong, Salah-Eddine Lamhamedi-Cherradi, Joseph A Ludwig.
      Primary bone cancers (PBC) belong to the family of mesenchymal tumors classified based on their cellular origin, extracellular matrix, genetic regulation, and epigenetic modification. The three major PBC types, Ewing sarcoma, osteosarcoma, and chondrosarcoma, are frequently aggressive tumors, highly metastatic, and typically occur in children and young adults. Despite their distinct origins and pathogenesis, these sarcoma subtypes rely upon common signaling pathways to promote tumor progression, metastasis, and survival. The IGF/PI3K/mTOR and AXL/YAP/TAZ pathways, in particular, have gained significant attention recently given their ties to oncogenesis, cell fate and differentiation, metastasis, and drug resistance. Naturally, these pathways - and their protein constituents - have caught the eye of the pharmaceutical industry, and a wide array of small molecule inhibitors and antibody drug-conjugates have emerged. Here, we review how the IGF/PI3K/mTOR and AXL/YAP/TAZ pathways promote PBC and highlight the drug candidates under clinical trial investigation.
    Keywords:  AXL; Bone cancer; Chondrosarcoma; Ewing sarcoma; IGF-1R; Osteosarcoma; PI3K; mTOR
    DOI:  https://doi.org/10.1016/j.jbo.2022.100419
  8. Front Physiol. 2022 ;13 706003
    Histone Deacetylases as Modulators of the Crosstalk Between Skeletal Muscle and Other Organs.
    Alessandra Renzini, Marco D'Onghia, Dario Coletti, Viviana Moresi.
      Skeletal muscle plays a major role in controlling body mass and metabolism: it is the most abundant tissue of the body and a major source of humoral factors; in addition, it is primarily responsible for glucose uptake and storage, as well as for protein metabolism. Muscle acts as a metabolic hub, in a crosstalk with other organs and tissues, such as the liver, the brain, and fat tissue. Cytokines, adipokines, and myokines are pivotal mediators of such crosstalk. Many of these circulating factors modulate histone deacetylase (HDAC) expression and/or activity. HDACs form a numerous family of enzymes, divided into four classes based on their homology to their orthologs in yeast. Eleven family members are considered classic HDACs, with a highly conserved deacetylase domain, and fall into Classes I, II, and IV, while class III members are named Sirtuins and are structurally and mechanistically distinct from the members of the other classes. HDACs are key regulators of skeletal muscle metabolism, both in physiological conditions and following metabolic stress, participating in the highly dynamic adaptative responses of the muscle to external stimuli. In turn, HDAC expression and activity are closely regulated by the metabolic demands of the skeletal muscle. For instance, NAD+ levels link Class III (Sirtuin) enzymatic activity to the energy status of the cell, and starvation or exercise affect Class II HDAC stability and intracellular localization. SUMOylation or phosphorylation of Class II HDACs are modulated by circulating factors, thus establishing a bidirectional link between HDAC activity and endocrine, paracrine, and autocrine factors. Indeed, besides being targets of adipo-myokines, HDACs affect the synthesis of myokines by skeletal muscle, altering the composition of the humoral milieu and ultimately contributing to the muscle functioning as an endocrine organ. In this review, we discuss recent findings on the interplay between HDACs and circulating factors, in relation to skeletal muscle metabolism and its adaptative response to energy demand. We believe that enhancing knowledge on the specific functions of HDACs may have clinical implications leading to the use of improved HDAC inhibitors for the treatment of metabolic syndromes or aging.
    Keywords:  HDAC inhibitors (HDACi); HDACs; epigenetics; soluble factors; tissue crosstalk
    DOI:  https://doi.org/10.3389/fphys.2022.706003
  9. J Exp Clin Cancer Res. 2022 Mar 08. 41(1): 87
    miR-3189-targeted GLUT3 repression by HDAC2 knockdown inhibits glioblastoma tumorigenesis through regulating glucose metabolism and proliferation.
    Sungmin Kwak, Seung-Ho Park, Sung-Hak Kim, Gi-Jun Sung, Ji-Hye Song, Ji-Hoon Jeong, Hyunhee Kim, Chang Hoon Ha, Seong Who Kim, Kyung-Chul Choi.
      BACKGROUND: Epigenetic regulations frequently appear in Glioblastoma (GBM) and are highly associated with metabolic alterations. Especially, Histone deacetylases (HDACs) correlates with the regulation of tumorigenesis and cell metabolism in GBM progression, and HDAC inhibitors report to have therapeutic efficacy in GBM and other neurological diseases; however, GBM prevention and therapy by HDAC inhibition lacks a mechanism in the focus of metabolic reprogramming.METHODS: HDAC2 highly express in GBM and is analyzed in TCGA/GEPIA databases. Therefore, HDAC2 knockdown affects GBM cell death. Analysis of RNA sequencing and qRT-PCR reveals that miR-3189 increases and GLUT3 decreases by HDAC2 knockdown. GBM tumorigenesis also examines by using in vivo orthotopic xenograft tumor models. The metabolism change in HDAC2 knockdown GBM cells measures by glucose uptake, lactate production, and OCR/ECAR analysis, indicating that HDAC2 knockdown induces GBM cell death by inhibiting GLUT3.
    RESULTS: Notably, GLUT3 was suppressed by increasing miR-3189, demonstrating that miR-3189-mediated GLUT3 inhibition shows an anti-tumorigenic effect and cell death by regulating glucose metabolism in HDAC2 knockdown GBM.
    CONCLUSIONS: Our findings will demonstrate the central role of HDAC2 in GBM tumorigenesis through the reprogramming of glucose metabolism by controlling miR-3189-inhibited GLUT3 expression, providing a potential new therapeutic strategy for GBM treatment.
    Keywords:  GLUT3; Glioblastoma; Glioma stem cells; HDAC2; miR-3189
    DOI:  https://doi.org/10.1186/s13046-022-02305-5
  10. Pharmacol Res. 2022 Mar 05. pii: S1043-6618(22)00104-9. [Epub ahead of print] 106159
    Focus on the classical and non-classical functions of EZH2: Guide the development of inhibitors and degraders.
    Qiangsheng Zhang, Hongling Yang, Qiang Feng, Jiaying Cao, Yiqian Zhang, Lu Li, Luoting Yu.
      Enhancer of zeste homologue 2 (EZH2, also known as KMT6A) is found to be a member of the histone lysine methyltransferase family. An increasing number of studies have shown that in addition to methylating histones, EZH2 plays a vital role in a variety of ways. The methylated substrates of EZH2 also include GATA4, AR/AR-related proteins, STAT3, Talin protein, and RORα. Meanwhile, EZH2 has been reported to form complexes with some proteins to perform other important biological functions as well as methylation. These complexes include: the EZH2-RelA-RelB complex, EZH2-ER-β-catenin complex, and β-catenin-PAF-EZH2-Mediator complex. Herein, we focus on the classical and non-classical functions of EZH2, and summarize anti-EZH2 therapeutic strategies. Finally, we highlight that understanding the physiological and pathological functions of EZH2 in specific indications can help the development of inhibitors or degraders.
    Keywords:  Covalent inhibitors; Degraders; Dual inhibitors; EZH2; Epigenetics; Histone modification; PPI inhibitors
    DOI:  https://doi.org/10.1016/j.phrs.2022.106159
  11. iScience. 2022 Mar 18. 25(3): 103917
    Single cell analysis of mechanical properties and EMT-related gene expression profiles in cancer fingers.
    Heng Zou, Zihan Yang, Yuen-San Chan, Sung-King Au Yeung, Md Kowsar Alam, Tongxu Si, Tao Xu, Mengsu Yang.
      Collective cell migration is associated with cancer metastasis. Cancer fingers are formed when groups of migrating cancer cells follow the leader cells in the front. Epithelial to mesenchymal transition (EMT) is a critical process of cancer metastasis. However, the role of EMT in cancer finger formation remains unclear. In this work, we investigated the EMT-associated mechanical properties and gene expression at single-cell levels in non-small lung cancer fingers. We found that leader cells were more elastic and less sticky than follower cells. Spatial EMT-related gene expression profiling in cancer fingers revealed cellular heterogeneity. Particularly, SNAIL and VIM were found to be two key genes that positively correlated with leader cell phenotypes and controlled cancer finger formation. Silencing either SNAIL or VIM, decreased cancer cell elasticity, cancer finger formation and migration, and increased adhesiveness. These findings indicated that SNAIL and VIM are two driver genes for cancer finger formation.
    Keywords:  Cancer; Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.103917
  12. Mol Cancer Res. 2022 Mar 04. pii: molcanres.0923.2021. [Epub ahead of print]
    Constitutive β-catenin overexpression represses lncRNA MIR100HG transcription via HDAC6-mediated histone modification in colorectal cancer.
    Jian Peng, Yiming Ma, Xinhua Zhao, Xu Yang, Hongying Wang.
      Wnt/β-catenin signaling plays a critical role in colonic carcinogenesis. However, non-coding RNAs (ncRNAs) transcriptionally regulated by β-catenin are largely unknown. Herein, we found that lncRNA MIR100HG (lnc-MIR100HG) negatively correlated with target genes of β-catenin from The Cancer Genome Atlas colorectal carcinoma (CRC) database, which was verified in 48 paired CRC specimens. In addition, constitutive overexpression of β-catenin decreased primary and mature lnc-MIR100HG levels, while blockage of β-catenin activity with siRNA or inhibitors significantly increased their expression. DNA pull-down and chromatin immunoprecipitation revealed the binding of β-catenin/TCF4 to the MIR100HG promoter. Moreover, β-catenin forced expression reduced the enrichment of H3K27Ac, an active transcription marker, on the promoter, while β-catenin inhibition reversed this effect. Furthermore, HDAC6 was recruited to the MIR100HG promoter and downregulated H3K27Ac enrichment in a β-catenin-dependent manner. Besides, HDAC6 was upregulated and negatively correlated with lnc-MIR100HG in CRC specimens. Functional studies showed that lnc-MIR100HG overexpression induced cell cycle G0/G1 arrest and repressed cell proliferation via p57 upregulation in vitro and in vivo. Taken together, we found that ectopic β-catenin transcriptionally repressed lnc-MIR100HG expression through HDAC6-mediated histone modification in CRC. Lnc-MIR100HG regulates the cell cycle through p57. Implications: It provides a novel downstream mechanism highlighting β-catenin action during colon carcinogenesis and may shed light for further therapeutic approaches.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-21-0923
  13. Anticancer Drugs. 2022 Apr 01. 33(4): 352-361
    Yes-associated protein 1 exerts its tumor-promoting effects and increases cisplatin resistance in tongue squamous cell carcinoma cells by dysregulating Hippo signal pathway.
    Hua Guan, Linlin Deng.
      Tongue squamous cell carcinoma (TSCC) has been well-known for its high metastasis and poor prognosis, but the molecular mechanisms of TSCC pathogenesis and chemoresistance are still largely unknown. Thus, the present study aimed to identify the involvement of a classic Hippo/Yes-associated protein 1 (YAP1) pathway in regulating TSCC progression and cisplatin (DDP) resistance. DDP-resistant TSCC cell lines were established by gradual exposure to DDP. Through western blot analysis, the protein expression of Hippo/YAP1 axis in TSCC tissues and cell lines was detected separately. Then, YAP1 was inhibited or overexpressed in TSCC cells. Cell viability and drug resistance were evaluated by cell counting kit-8 method, colony formation assay and Trypan blue staining assay. Cell migration ability was measured by Transwell assay. The Hippo pathway was dysregulated, and YAP1 was upregulated and dephosphorylated in the TSCC tissues or DDP-resistant cell lines, compared with normal tissues or DDP-sensitive cells. YAP1 knockdown inhibited cell proliferation, colony formation ability and migration, whereas overexpression of YAP1 exacerbated these malignant characteristics. YAP1 knockdown increased DDP-sensitivity by reducing the RAD51-mediated DNA damage repair behavior under DDP intervention in the DDP-resistant TSCC cells. Conversely, YAP1 overexpression significantly increased DDP-resistance by enhancing the RAD51-mediated DNA damage repair behavior under DDP intervention in the DDP-sensitive TSCC cells. In a word, upregulation and dephosphorylation of YAP1 caused dysregulation of the tumor-inhibiting Hippo pathway, resulting in the aggressiveness and DDP resistance in TSCC.
    DOI:  https://doi.org/10.1097/CAD.0000000000001269
  14. Cancers (Basel). 2022 Feb 26. pii: 1221. [Epub ahead of print]14(5):
    Epigenetic Regulation: A Link between Inflammation and Carcinogenesis.
    Bianca Vezzani, Marianna Carinci, Maurizio Previati, Stefania Giacovazzi, Mario Della Sala, Roberta Gafà, Giovanni Lanza, Mariusz R Wieckowski, Paolo Pinton, Carlotta Giorgi.
      Epigenetics encompasses a group of dynamic, reversible, and heritable modifications that occur within cells that are independent of gene mutations. These alterations are highly influenced by the environment, from the environment that surrounds the human being to the internal microenvironments located within tissues and cells. The ways that pigenetic modifications promote the initiation of the tumorigenic process have been widely demonstrated. Similarly, it is well known that carcinogenesis is supported and prompted by a strong proinflammatory environment. In this review, we introduce our report of a proinflammatory microenvironment that encircles the tumor core but can be responsible for the induction of epigenetic drift. At the same time, cancer cells can alter their epigenetic profile to generate a positive loop in the promotion of the inflammatory process. Therefore, an in-depth understanding of the epigenetic networks between the tumor microenvironment and cancer cells might highlight new targetable mechanisms that could prevent tumor progression.
    Keywords:  carcinogenesis; epigenetics; inflammation; tumor microenvironment
    DOI:  https://doi.org/10.3390/cancers14051221
  15. Acc Chem Res. 2022 Mar 10.
    Participation of Histones in DNA Damage and Repair within Nucleosome Core Particles: Mechanism and Applications.
    Mengtian Ren, Marc M Greenberg, Chuanzheng Zhou.
      ConspectusDNA is damaged by various endogenous and exogenous sources, leading to a diverse group of reactive intermediates that yield a complex mixture of products. The initially formed products are often metastable and can react to yield lesions that are more biologically deleterious. Mechanistic studies are frequently carried out on free DNA as the substrate. The observations do not necessarily reflect the reaction environment inside human cells where genomic DNA is condensed as chromatin in the nucleus. Chromatin is made up of monomeric structural units called nucleosomes, which are comprised of DNA wrapped around an octameric core of histone proteins (two copies each of histones H2A, H2B, H3, and H4).This account presents a summary of our work in the past decade on the mechanistic studies of DNA damage and repair in reconstituted nucleosome core particles (NCPs). A series of metastable lesions and reactive intermediates, such as abasic sites (AP), N7-methyl-2'-deoxyguanosine (MdG), and 2'-deoxyadenosin-N6-yl radical (dA•), have been independently generated in a site-specific manner in bottom-up-synthesized NCPs. Detailed mechanistic studies on these NCPs revealed that histones actively participate in DNA damage and repair processes in diverse ways. For instance, nucleophilic residues in the flexible histone N-terminal tails, such as Lys and N-terminal α-amine, react with electrophilic DNA damage and reactive intermediates. In some cases, transient intermediates are produced, leading to the promotion or suppression of damage and repair processes. In other examples, reactions with histones yield reversible or stable DNA-protein cross-links (DPCs). Histones also utilize acidic and basic residues, such as histidine and aspartic acid, to catalyze DNA strand cleavage through general acid/base catalysis. Alternatively, a Tyr in histone plays a vital role in nucleosomal DNA damage and repair via radical transfer. Finally, the reactivity discovered during the mechanistic studies has facilitated the development of new reagents and methods with applications in biotechnology.This research has enriched our knowledge of the roles of histone proteins in DNA damage and repair and their contributions to epigenetics and may have significant biological implications. The residues in histone N-terminal tails that react with DNA lesions also play pivotal roles in regulating the structure and function of chromatin, indicating that there may be cross-talk between DNA damage and repair in eukaryotic cells and epigenetic regulation. Also, in view of the biased amino acid composition of histones, these results provide hints about how the proteins have evolved to minimize their deleterious effects but maximize beneficial ones for maintaining genome integrity. Finally, previously unreported DPCs and histone post-translational modifications have been discovered through this research. The effects of these newly identified lesions on the structure and function of chromatin and their fates inside cells remain to be elucidated.
    DOI:  https://doi.org/10.1021/acs.accounts.2c00041
  16. Transl Cancer Res. 2022 Jan;11(1): 262-275
    A narrative review for the Hippo-YAP pathway in cancer survival and immunity: the Yin-Yang dynamics.
    Ruochong Wang, Guiquan Zhu.
      The Hippo-YAP pathway is fast becoming a key instrument in regulating cancers. Binary oppositions, also known as the Yin-Yang dynamics in Chinese, have emerged in its effects. Some oppositions are attributable to in vitro and in vivo experimental conditions, some are due to differences between cancers or species, some are derived from its inherent duality endowed by upstream and downstream signaling, and some are yet unresolved mysteries. However, as bewildering they are, few have been noticed and defined so far. In this review, we first look back on the Hippo pathway which was initially identified more than a decade ago. We then focus on tumor biology, especially some latest popular mechanisms that regulate tumor cell survival, such as ferroptosis, autophagy, and apoptosis. The third chapter is concerned with the findings of the relationship between the Hippo pathway and tumor immunity on the microenvironment in which tumor cells progress. In each of these main sections the contradictory points of the Hippo pathway are elucidated and thoroughly examined. On one hand, the Yin-Yang dynamics of the Hippo pathway brings about considerable challenges for current research; on the other hand, this work will generate fresh insight into it and offer opportunities for subsequent drug development for cancer and regenerative medicine.
    Keywords:  Hippo pathway; apoptosis; autophagy; cancer; ferroptosis
    DOI:  https://doi.org/10.21037/tcr-21-1843
  17. J Exp Clin Cancer Res. 2022 Mar 11. 41(1): 91
    HDAC7 promotes NSCLC proliferation and metastasis via stabilization by deubiquitinase USP10 and activation of β-catenin-FGF18 pathway.
    Kai Guo, Zhiqiang Ma, Yujiao Zhang, Lu Han, Changjian Shao, Yingtong Feng, Fei Gao, Shouyin Di, Zhipei Zhang, Jiao Zhang, Fabrizio Tabbò, Simon Ekman, Kenichi Suda, Federico Cappuzzo, Jing Han, Xiaofei Li, Xiaolong Yan.
      BACKGROUND: Histone deacetylases (HDACs) play crucial roles in cancers, but the role and mechanism of HDAC7 in NSCLC have not been fully understood.METHODS: A total of 319 patients with non-small cell lung cancer (NSCLC) who underwent surgery were enrolled in this study. Immunohistochemistry and Kaplan-Meier survival analysis were performed to investigate the relationship between HDAC7, fibroblast growth factor 18 (FGF18) expression, and clinicopathologic characteristics. Cell functional experiments were implemented both in vivo and in vitro to investigate the effects on NSCLC cell proliferation and metastasis. Recombinant lentivirus-meditated in vivo gene overexpression or knockdown, real-time polymerase chain reaction (PCR), western blotting, and coimmunoprecipitation assays were applied to clarify the underlying molecular mechanism of HDAC7 in promoting NSCLC progression.
    RESULTS: The elevated expression of HDAC7 or FGF18 was positively correlated with poor prognosis, tumor-node-metastasis (TNM) stage, and tumor differentiation of NSCLC patients. NSCLC patients with co-expressed HDAC7 and FGF18 suffered the worst prognosis. HDAC7 overexpression promoted NSCLC proliferation and metastasis by upregulating FGF18. Conversely, overexpression of FGF18 reversed the attenuated ability in tumor growth and metastasis mediated by downregulating HDAC7. In terms of mechanism, our results suggested that the interaction of HDAC7 with β-catenin caused decreased β-catenin acetylation level at Lys49 and decreased phosphorylation level at Ser45. As a consequence, the HDAC7-mediated posttranslational modification of β-catenin facilitated nuclear transfer and activated FGF18 expression via binding to TCF4. Furthermore, deubiquitinase USP10 interacted with and stabilized HDAC7. The suppression of USP10 significantly accelerated the degradation of HDAC7 and weakened NSCLC growth and migration.
    CONCLUSIONS: Our findings reveal that HDAC7 promotes NSCLC progression through being stabilized by USP10 and activating the β-catenin-FGF18 pathway. Targeting this novel pathway may be a promising strategy for further developments in NSCLC therapy.
    Keywords:  FGF18; HDAC7; NSCLC; USP10; β-catenin
    DOI:  https://doi.org/10.1186/s13046-022-02266-9
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