bims-ectoca 2023-10-01 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2023–10–01
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science

Lysine Demethylation in Pathogenesis.
Drug-tolerant persister cells in cancer: the cutting edges and future directions.
Stressed Hippo kinase turns to autophagy.
KDM5 Lysine Demethylases in Pathogenesis, from Basic Science Discovery to the Clinic.
YAP mediates resistance to EGF-induced apoptosis in EGFR-mutated non-small cell lung cancer cells.
Verteporfin Exerts Anticancer Effects and Reverses Resistance to Paclitaxel via Inducing Ferroptosis in Esophageal Squamous Cell Cancer Cells.
Histone Methyltransferases as a New Target for Epigenetic Action of Vorinostat.
Effective targeting of breast cancer by the inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells.
Mapping the Single-cell Differentiation Landscape of Osteosarcoma.
ChromNetMotif: a Python tool to extract chromatin-sate marked motifs in a chromatin interaction network.
Bone-targeting exosome nanoparticles activate Keap1 / Nrf2 / GPX4 signaling pathway to induce ferroptosis in osteosarcoma cells.
Possible Role of IL-6R/STAT3/MiRNA-34a Feedback Loop in Osteosarcoma.

Adv Exp Med Biol. 2023 ;1433 1-14

Lysine Demethylation in Pathogenesis.

Jian Cao, Qin Yan.

  Epigenetics has major impact on normal development and pathogenesis. Regulation of histone methylation on lysine and arginine residues is a major epigenetic mechanism and affects various processes including transcription and DNA repair. Histone lysine methylation is reversible and is added by histone lysine methyltransferases and removed by histone lysine demethylases. As these enzymes are also capable of writing or erasing lysine modifications on non-histone substrates, they were renamed to lysine demethylases (KDMs) in 2007. Since the discovery of the first lysine demethylase LSD1/KDM1A in 2004, eight more subfamilies of lysine demethylases have been identified and further characterized. The joint efforts by academia and industry have led to the development of potent and specific small molecule inhibitors of KDMs for treatment of cancer and several other diseases. Some of these inhibitors have already entered clinical trials since 2013, less than 10 years after the discovery of the first KDM. In this chapter, we briefly summarize the major roles of histone demethylases in normal development and human diseases and the efforts to target these enzymes to treat various diseases.

Keywords:  Amine oxidase; Cancer; Histone demethylase; Histone methylation; Hydroxylase; JmjC; KDM; KDM inhibitor; LSD1; Lysine demethylase

DOI:  https://doi.org/10.1007/978-3-031-38176-8_1
Nat Rev Clin Oncol. 2023 Sep 25.

Drug-tolerant persister cells in cancer: the cutting edges and future directions.

Yi Pu, Lu Li, Haoning Peng, Lunxu Liu, Dominique Heymann, Caroline Robert, François Vallette, Shensi Shen.

Drug-tolerant persister (DTP) cell populations were originally discovered in antibiotic-resistant bacterial biofilms. Similar populations with comparable features have since been identified among cancer cells and have been linked with treatment resistance that lacks an underlying genomic alteration. Research over the past decade has improved our understanding of the biological roles of DTP cells in cancer, although clinical knowledge of the role of these cells in treatment resistance remains limited. Nonetheless, targeting this population is anticipated to provide new treatment opportunities. In this Perspective, we aim to provide a clear definition of the DTP phenotype, discuss the underlying characteristics of these cells, their biomarkers and vulnerabilities, and encourage further research on DTP cells that might improve our understanding and enable the development of more effective anticancer therapies.

DOI: https://doi.org/10.1038/s41571-023-00815-5
Sci Signal. 2023 Sep 26. 16(804): eadk9489

Stressed Hippo kinase turns to autophagy.

Leslie K Ferrarelli.

The Hippo kinase MAP4K2 takes a YAP-independent path to tolerating energy stress.

DOI: https://doi.org/10.1126/scisignal.adk9489
Adv Exp Med Biol. 2023 ;1433 113-137

KDM5 Lysine Demethylases in Pathogenesis, from Basic Science Discovery to the Clinic.

Shang-Min Zhang, Jian Cao, Qin Yan.

  The histone lysine demethylase 5 (KDM5) family proteins are Fe2+ and α-ketoglutarate-dependent dioxygenases, with jumonji C (JmjC) domain as their catalytic core and several plant homeodomains (PHDs) to bind different histone methylation marks. These enzymes are capable of demethylating tri-, di- and mono-methylated lysine 4 in histone H3 (H3K4me3/2/1), the key epigenetic marks for active chromatin. Thus, this H3K4 demethylase family plays critical roles in cell fate determination during development as well as malignant transformation. KDM5 demethylases have both oncogenic and tumor suppressive functions in a cancer type-dependent manner. In solid tumors, KDM5A/B are generally oncogenic, whereas KDM5C/D have tumor suppressive roles. Their involvement in de-differentiation, cancer metastasis, drug resistance, and tumor immunoevasion indicated that KDM5 family proteins are promising drug targets for cancer therapy. Significant efforts from both academia and industry have led to the development of potent and selective KDM5 inhibitors for preclinical experiments and phase I clinical trials. However, a better understanding of the roles of KDM5 demethylases in different physiological and pathological conditions is critical for further developing KDM5 modulators for clinical applications.

Keywords:  Antitumor immunity; Cancer; Drug resistance; Histone demethylase; Jumonji; KDM5; Stem cell

DOI:  https://doi.org/10.1007/978-3-031-38176-8_6
Biochem Biophys Res Commun. 2023 Sep 23. pii: S0006-291X(23)01103-8. [Epub ahead of print]681 120-126

YAP mediates resistance to EGF-induced apoptosis in EGFR-mutated non-small cell lung cancer cells.

Maako Nakajima, Kentaro Tanaka, Yasuto Yoneshima, Sho Yamashita, Daisuke Shibahara, Eiji Iwama, Isamu Okamoto.

  Mechanisms underlying the growth and survival of non-small cell lung cancer (NSCLC) cells positive for activating mutations of the epidermal growth factor receptor gene (EGFR) have remained unclear. We here examined the functional relation between such mutant forms of EGFR and Yes-associated protein (YAP), a transcriptional coactivator of the Hippo signaling pathway that regulates cell proliferation and survival. Under the condition of serum deprivation, epidermal growth factor (EGF) induced activation of YAP in NSCLC cell lines positive for mutated EGFR but not in those wild type (WT) for EGFR. Similar EGF-induced activation of YAP was apparent in A549 lung cancer cells forcibly expressing mutant EGFR but not in those overexpressing the WT receptor. Furthermore, EGF induced apoptotic cell death in serum-deprived A549 cells overexpressing the WT form of EGFR but not in those expressing mutant EGFR, and knockdown of YAP rendered the latter cells sensitive to this effect of EGF. Our results thus suggest that activation of YAP mediates resistance of EGFR-mutated NSCLC cells to EGF-induced apoptosis and thereby contributes specifically to the survival of such cells.

Keywords:  Apoptosis; Epidermal growth factor (EGF); Epidermal growth factor receptor (EGFR); Hippo pathway; Non-small cell lung cancer; Yes-associated protein (YAP)

DOI:  https://doi.org/10.1016/j.bbrc.2023.09.067
Mol Biotechnol. 2023 Sep 26.

Verteporfin Exerts Anticancer Effects and Reverses Resistance to Paclitaxel via Inducing Ferroptosis in Esophageal Squamous Cell Cancer Cells.

Xue-Wei Wang, Zi-Yi Yang, Ting Li, Xin-Ran Zhao, Xiao-Zhong Li, Xiao-Xia Wang.

  Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. Ferroptosis is a new form of regulated cell death and targeting ferroptosis provides a novel therapeutic approach for human cancers. Verteporfin (VP) has been identified as a Yes-associated protein (YAP) inhibitor for treatment of several human cancers. However, it remains unclear whether VP exerts anticancer activity by inducing ferroptosis in ESCC cells. In the current study, we found that VP reduced cell viability and led to cell death in ESCC cell lines (KYSE150 and KYSE30) by inhibiting YAP expression. Subsequently, the findings revealed that VP treatment triggered significant ferroptosis events, including accumulation of Fe2+, reactive oxygen species (ROS) and malondialdehyde (MDA), reduction of mitochondrial membrane potential (MMP), glutathione (GSH) and glutathione peroxidase 4 (GPX4) expression. Further study showed that the effects of ESCC cell proliferation and death caused by VP could be reversed by ferroptosis inhibitor ferrostatin-1 (Fer-1). Moreover, VP enhanced the chemosensitivity of ESCC resistant cells to paclitaxel (PTX). And VP combined with PTX can synergistically inhibit cell proliferation and induce cell death by triggering ferroptosis of PTX-resistant cells. All these data suggested that VP suppressed ESCC cell survival and reversed resistance to PTX through inducing ferroptosis, which may provide a promising therapeutic strategy for ESCC.

Keywords:  Chemoresistance; Esophageal squamous cell carcinoma; Ferroptosis; Verteporfin

DOI:  https://doi.org/10.1007/s12033-023-00891-z
Biochemistry (Mosc). 2023 Jul;88(7): 968-978

Histone Methyltransferases as a New Target for Epigenetic Action of Vorinostat.

Varvara Maksimova, Julia Makus, Valeriia Popova, Anzhelika Prus, Olga Usalka, Ekaterina Trapeznikova, Ekaterina Zhidkova, Gennady Belitsky, Marianna Yakubovskaya, Kirill Kirsanov.

  Epigenetic genome regulation during malignant cell transformation is characterized by the aberrant methylation and acetylation of histones. Vorinostat (SAHA) is an epigenetic modulator actively used in clinical oncology. The antitumor activity of vorinostat is commonly believed to be associated with the inhibition of histone deacetylases, while the impact of this drug on histone methylation has been poorly studied. Using HeLa TI cells as a test system allowing evaluation of the effect of epigenetically active compounds from the expression of the GFP reporter gene and gene knockdown by small interfering RNAs, we showed that vorinostat not only suppressed HDAC1, but also reduced the activity of EZH2, SUV39H1, SUV39H2, and SUV420H1. The ability of vorinostat to suppress expression of EZH2, SUV39H1/2, SUV420H1 was confirmed by Western blotting. Vorinostat also downregulated expression of SUV420H2 and DOT1L enzymes. The data obtained expand our understanding of the epigenetic effects of vorinostat and demonstrate the need for a large-scale analysis of its activity toward other enzymes involved in the epigenetic genome regulation. Elucidation of the mechanism underlying the epigenetic action of vorinostat will contribute to its more proper use in the treatment of tumors with an aberrant epigenetic profile.

Keywords:  DOT1L; EZH2; HeLa TI test system; SAHA; SUV39H1; SUV39H2; SUV420H1; SUV420H2; histone methylation; histone methyltransferase (HMT); malignant neoplasms with aberrant epigenetic profile; vorinostat

DOI:  https://doi.org/10.1134/S000629792307009X
Drug Resist Updat. 2023 Sep 17. pii: S1368-7646(23)00090-0. [Epub ahead of print]71 101007

Effective targeting of breast cancer by the inhibition of P-glycoprotein mediated removal of toxic lipid peroxidation byproducts from drug tolerant persister cells.

Kornélia Szebényi, András Füredi, Eszter Bajtai, Sai Nagender Sama, Agnes Csiszar, Balázs Gombos, Pál Szabó, Michael Grusch, Gergely Szakács.

  Therapy resistance has long been considered to occur through the selection of pre-existing clones equipped to survive and quickly regrow, or through the acquisition of mutations during chemotherapy. Here we show that following in vitro treatment by chemotherapy, epithelial breast cancer cells adopt a transient drug tolerant phenotype characterized by cell cycle arrest, epithelial-to-mesenchymal transition (EMT) and the reversible upregulation of the multidrug resistance (MDR) efflux transporter P-glycoprotein (P-gp). The drug tolerant persister (DTP) state is reversible, as cells eventually resume proliferation, giving rise to a cell population resembling the initial, drug-naïve cell lines. However, recovery after doxorubicin treatment is almost completely eliminated when DTP cells are cultured in the presence of the P-gp inhibitor Tariquidar. Mechanistically, P-gp contributes to the survival of DTP cells by removing reactive oxygen species-induced lipid peroxidation products resulting from doxorubicin exposure. In vivo, prolonged administration of Tariquidar during doxorubicin treatment holidays resulted in a significant increase of the overall survival of Brca1-/-;p53-/- mammary tumor bearing mice. These results indicate that prolonged administration of a P-gp inhibitor during drug holidays would likely benefit patients without the risk of aggravated side effects related to the concomitantly administered toxic chemotherapy. Effective targeting of DTPs through the inhibition of P-glycoprotein may result in a paradigm shift, changing the focus from countering drug resistance mechanisms to preventing or delaying therapy resistance.

Keywords:  Drug-tolerant persister; Genetically engineered mouse model of cancer; Multidrug resistance; P-glycoprotein; Tariquidar; Triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.drup.2023.101007
bioRxiv. 2023 Sep 14. pii: 2023.09.13.555156. [Epub ahead of print]

Mapping the Single-cell Differentiation Landscape of Osteosarcoma.

Danh D Truong, Corey Weistuch, Kevin A Murgas, Joseph O Deasy, Antonios G Mikos, Allen Tannenbaum, Joseph Ludwig.

The genetic and intratumoral heterogeneity observed in human osteosarcomas (OS) poses challenges for drug development and the study of cell fate, plasticity, and differentiation, processes linked to tumor grade, cell metastasis, and survival. To pinpoint errors in OS differentiation, we transcriptionally profiled 31,527 cells from a tissue-engineered model that directs MSCs toward adipogenic and osteoblastic fates. Incorporating pre-existing chondrocyte data, we applied trajectory analysis and non-negative matrix factorization (NMF) to generate the first human mesenchymal differentiation atlas. This 'roadmap' served as a reference to delineate the cellular composition of morphologically complex OS tumors and quantify each cell's lineage commitment. Projecting these signatures onto a bulk RNA-seq OS dataset unveiled a correlation between a stem-like transcriptomic phenotype and poorer survival outcomes. Our study takes the critical first step in accurately quantifying OS differentiation and lineage, a prerequisite to better understanding global differentiation bottlenecks that might someday be targeted therapeutically.
Statement of Significance: OS treatment kills proliferating cells without addressing the root cause: dysregulated differentiation. By deconvolving OS tumors by cell type and differentiation archetype, we identified core gene sets linked to cell fate and patient survival. The ability to quantify, and eventually modulate, such archetypes facilitate a novel OS-specific drug-screening strategy.

DOI: https://doi.org/10.1101/2023.09.13.555156
Bioinform Adv. 2023 ;3(1): vbad126

ChromNetMotif: a Python tool to extract chromatin-sate marked motifs in a chromatin interaction network.

Benjamin Soibam.

Motivation: Analysis of network motifs is crucial to studying the robustness, stability, and functions of complex networks. Genome organization can be viewed as a biological network that consists of interactions between different chromatin regions. These interacting regions are also marked by epigenetic or chromatin states which can contribute to the overall organization of the chromatin and proper genome function. Therefore, it is crucial to integrate the chromatin states of the nodes when performing motif analysis in chromatin interaction networks. Even though there has been increasing production of chromatin interaction and genome-wide epigenetic modification data, there is a lack of publicly available tools to extract chromatin state-marked motifs from genome organization data.
Results: We develop a Python tool, ChromNetMotif, offering an easy-to-use command line interface to extract chromatin-state-marked motifs from a chromatin interaction network. The tool can extract occurrences, frequencies, and statistical enrichment of the chromatin state-marked motifs. Visualization files are also generated which allow the user to interpret the motifs easily. ChromNetMotif also allows the user to leverage the features of a multicore processor environment to reduce computation time for larger networks. The output files generated can be used to perform further downstream analysis. ChromNetMotif aims to serve as an important tool to comprehend the interplay between epigenetics and genome organization.
Availability and implementation: ChromNetMotif is available at https://github.com/lncRNAAddict/ChromNetworkMotif.

DOI: https://doi.org/10.1093/bioadv/vbad126
J Nanobiotechnology. 2023 Sep 30. 21(1): 355

Bone-targeting exosome nanoparticles activate Keap1 / Nrf2 / GPX4 signaling pathway to induce ferroptosis in osteosarcoma cells.

Wenkai Chen, Zongguang Li, Naichun Yu, Linlin Zhang, Hongyu Li, Yongjie Chen, Fengqing Gong, Wenping Lin, Xu He, Siyuan Wang, Yue Wu, Guangrong Ji.

   BACKGROUND: In recent years, the development of BMSCs-derived exosomes (EXO) for the treatment of osteosarcoma (OS) is a safe and promising modality for OS treatment, which can effectively deliver drugs to tumor cells in vivo. However, the differences in the drugs carried, and the binding of EXOs to other organs limit their therapeutic efficacy. Therefore, improving the OS-targeting ability of BMSCs EXOs and developing new drugs is crucial for the clinical application of targeted therapy for OS.
RESULTS: In this study, we constructed a potential therapeutic nano platform by modifying BMSCs EXOs using the bone-targeting peptide SDSSD and encapsulated capreomycin (CAP) within a shell. These constructed nanoparticles (NPs) showed the ability of homologous targeting and bone-targeting exosomes (BT-EXO) significantly promotes cellular endocytosis in vitro and tumor accumulation in vivo. Furthermore, our results revealed that the constructed NPs induced ferroptosis in OS cells by prompting excessive accumulation of reactive oxygen species (ROS), Fe2+ aggregation, and lipid peroxidation and further identified the potential anticancer molecular mechanism of ferroptosis as transduced by the Keap1/Nrf2/GPX4 signaling pathway. Also, these constructed NP-directed ferroptosis showed significant inhibition of tumor growth in vivo with no significant side effects.
CONCLUSION: These results suggest that these constructed NPs have superior anticancer activity in mouse models of OS in vitro and in vivo, providing a new and promising strategy for combining ferroptosis-based chemotherapy with targeted therapy for OS.

Keywords:  Chemotherapy; Ferroptosis; Homologous targeting; Nrf2; Osteosarcoma

DOI:  https://doi.org/10.1186/s12951-023-02129-1
Asian Pac J Cancer Prev. 2023 Sep 01. pii: 90810. [Epub ahead of print]24(9): 3269-3274

Possible Role of IL-6R/STAT3/MiRNA-34a Feedback Loop in Osteosarcoma.

Marwa Fathy Amer, Abbas Mohamed, Abeer Ismail, Lamiaa Ali Bayoumi, Passant Essam Eldin Shibel, Ghada Nabil Elnaggar.

   OBJECTIVE: Osteosarcoma is considered the most common primary malignant tumor that develops from the primary osteoblasts. MiRNAs are small non-coding RNAs that play a key role in tumorigenesis. The aim of this study was to detect the possible relationship between expression levels of miRNA-34a and levels of Signal transducer and activator of transcription 3 (STAT3) and interleukin-6 receptor (IL-6R) in osteosarcoma and the possible role of this relationship in development of metastases in these patients.
METHODS: A total of thirty-six (36) bone samples were included in the study. They were divided into 3 groups: Group (I): Twelve normal bone samples as control group. Group (II): Twelve patients with non-metastatic osteosarcoma. Group (III): Twelve patients with metastatic osteosarcoma. MiRNA-34a expression levels were estimated using qRT-PCR. STAT3 and IL-6R levels were measured by ELISA.
RESULTS: Expression level of miRNA-34a was downregulated in osteosarcoma groups compared to control group. STAT3 and IL-6R levels were upregulated in osteosarcoma groups compared to control group. This difference in expression levels was found to be more significant in the metastatic group than the non-metastatic one (P<0.001 each). There was a significant positive correlation between STAT3 and IL-6R (r=0.868, P<0.001), and a significant inverse correlation between IL6 and miRNA-34a (r=-0.993, P<0.001).
CONCLUSION: miRNA-34a, STAT3 and IL-6R feedback loop could be a potential target for treatment of osteosarcoma and can be used as prognostic indicator for this disease.

Keywords:  IL-6R; Metastasis; STAT3; miRNA-34a; osteosarcoma

DOI:  https://doi.org/10.31557/APJCP.2023.24.9.3269