bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒05‒28
sixteen papers selected by
Ankita Daiya
BITS Pilani

  1. J Exp Clin Cancer Res. 2023 May 22. 42(1): 130
      Hippo signaling was first identified in Drosophila as a key controller of organ size by regulating cell proliferation and anti-apoptosis. Subsequent studies have shown that this pathway is highly conserved in mammals, and its dysregulation is implicated in multiple events of cancer development and progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) (hereafter YAP/TAZ) are the downstream effectors of the Hippo pathway. YAP/TAZ overexpression or activation is sufficient to induce tumor initiation and progression, as well as recurrence and therapeutic resistance. However, there is growing evidence that YAP/TAZ also exert a tumor-suppressive function in a context-dependent manner. Therefore, caution should be taken when targeting Hippo signaling in clinical trials in the future. In this review article, we will first give an overview of YAP/TAZ and their oncogenic roles in various cancers and then systematically summarize the tumor-suppressive functions of YAP/TAZ in different contexts. Based on these findings, we will further discuss the clinical implications of YAP/TAZ-based tumor targeted therapy and potential future directions.
    Keywords:  Hippo pathway; Oncogene; Targeted therapy; Tumor suppressor; YAP/TAZ
  2. Curr Issues Mol Biol. 2023 May 15. 45(5): 4344-4358
      Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells-the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance.
    Keywords:  cancer stem cells; driver mutations; osteosarcoma
  3. Epigenomes. 2023 May 17. pii: 10. [Epub ahead of print]7(2):
      Epigenetic modifications are heritable, reversible changes in histones or the DNA that control gene functions, being exogenous to the genomic sequence itself. Human diseases, particularly cancer, are frequently connected to epigenetic dysregulations. One of them is histone methylation, which is a dynamically reversible and synchronously regulated process that orchestrates the three-dimensional epigenome, nuclear processes of transcription, DNA repair, cell cycle, and epigenetic functions, by adding or removing methylation groups to histones. Over the past few years, reversible histone methylation has become recognized as a crucial regulatory mechanism for the epigenome. With the development of numerous medications that target epigenetic regulators, epigenome-targeted therapy has been used in the treatment of malignancies and has shown meaningful therapeutic potential in preclinical and clinical trials. The present review focuses on the recent advances in our knowledge on the role of histone demethylases in tumor development and modulation, in emphasizing molecular mechanisms that control cancer cell progression. Finally, we emphasize current developments in the advent of new molecular inhibitors that target histone demethylases to regulate cancer progression.
    Keywords:  cancer; cancer epitherapy; epigenetics; histone demethylase inhibitors; histone demethylases; transcription
  4. Cancer Sci. 2023 May 23.
      Chromatin is the fundamental structure of genomic DNA in eukaryotic cells. The nucleosome, the primary unit of chromatin, consists of DNA and histone proteins, and is important for the maintenance of genomic DNA. Histone mutations are present in many types of cancers, suggesting that chromatin and/or nucleosome structures could be closely related to cancer development. Histone modifications and histone variants are also involved in regulating chromatin and nucleosome structures. Chromatin structures are dynamically changed by nucleosome binding proteins. In this review article, we discuss the current progress toward understanding the relationship between chromatin structure and cancer development.
    Keywords:  DNA repair; chromatin; histone modification; histone mutation; nucleosome
  5. Chromosoma. 2023 May 20.
      Covalent histone modifications such as methylation, acetylation, phosphorylation, and other epigenetic modifications of the chromatin play an essential role in regulating eukaryotic cells of which most of these reactions are catalyzed by the enzymes. The binding energy of enzymes is often determined by experimental data via mathematical and statistical models due to specific modifications. Many theoretical models have been introduced to study histone modifications and reprogramming experiments in mammalian cells, in which all efforts in determining the affinity binding are essential part of the work. Here, we introduce a one-dimensional statistical Potts model to accurately determine the enzyme's binding free energy using the experimental data for various types of cells. We study the methylation of lysine 4 and 27 on histone H3 and suppose that each histone has one modification site with one of the seven states: H3K27me3, H3K27me2, H3K27me1, unmodified, H3K4me1, H3K4me2, and H3K4me3. Based on this model, the histone covalent modification is described. Moreover, by using simulation data, the histone's binding free energy and the energy of chromatin states are determined, when they are subject to changes from unmodified to active or repressive states, by finding the probability of the transition.
    Keywords:  Binding affinity; Chromatin; Epigenetics; Histone modifications; Methylation
  6. Proc Natl Acad Sci U S A. 2023 05 30. 120(22): e2211947120
      Cells integrate mechanical cues to direct fate specification to maintain tissue function and homeostasis. While disruption of these cues is known to lead to aberrant cell behavior and chronic diseases, such as tendinopathies, the underlying mechanisms by which mechanical signals maintain cell function are not well understood. Here, we show using a model of tendon de-tensioning that loss of tensile cues in vivo acutely changes nuclear morphology, positioning, and expression of catabolic gene programs, resulting in subsequent weakening of the tendon. In vitro studies using paired ATAC/RNAseq demonstrate that the loss of cellular tension rapidly reduces chromatin accessibility in the vicinity of Yap/Taz genomic targets while also increasing expression of genes involved in matrix catabolism. Concordantly, the depletion of Yap/Taz elevates matrix catabolic expression. Conversely, overexpression of Yap results in a reduction of chromatin accessibility at matrix catabolic gene loci, while also reducing transcriptional levels. The overexpression of Yap not only prevents the induction of this broad catabolic program following a loss of cellular tension, but also preserves the underlying chromatin state from force-induced alterations. Taken together, these results provide novel mechanistic details by which mechanoepigenetic signals regulate tendon cell function through a Yap/Taz axis.
    Keywords:  chromatin; epigenetics; mechanobiology
  7. Mol Cancer. 2023 05 20. 22(1): 85
      BACKGROUND: Enhancer of zeste homolog 2 (EZH2), the key catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed and plays an oncogenic role in various cancers through catalysis-dependent or catalysis-independent pathways. However, the related mechanisms contributing to ovarian cancer (OC) are not well understood.METHODS: The levels of EZH2 and H3K27me3 were evaluated in 105 OC patients by immunohistochemistry (IHC) staining, and these patients were stratified based on these levels. Canonical and noncanonical binding sites of EZH2 were defined by chromatin immunoprecipitation sequencing (ChIP-Seq). The EZH2 solo targets were obtained by integrative analysis of ChIP-Seq and RNA sequencing data. In vitro and in vivo experiments were performed to determine the role of EZH2 in OC growth.
    RESULTS: We showed that a subgroup of OC patients with high EZH2 expression but low H3K27me3 exhibited the worst prognosis, with limited therapeutic options. We demonstrated that induction of EZH2 degradation but not catalytic inhibition profoundly blocked OC cell proliferation and tumorigenicity in vitro and in vivo. Integrative analysis of genome-wide chromatin and transcriptome profiles revealed extensive EZH2 occupancy not only at genomic loci marked by H3K27me3 but also at promoters independent of PRC2, indicating a noncanonical role of EZH2 in OC. Mechanistically, EZH2 transcriptionally upregulated IDH2 to potentiate metabolic rewiring by enhancing tricarboxylic acid cycle (TCA cycle) activity, which contributed to the growth of OC.
    CONCLUSIONS: These data reveal a novel oncogenic role of EZH2 in OC and identify potential therapeutic strategies for OC by targeting the noncatalytic activity of EZH2.
    Keywords:  EZH2; IDH2; Metabolic rewiring; Ovarian cancer; TCA cycle
  8. Curr Issues Mol Biol. 2023 May 17. 45(5): 4375-4388
      AIM: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo.METHODS: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX.
    RESULTS: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01).
    CONCLUSION: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.
    Keywords:  actin cytoskeleton; atomic force microscopy; carbenoxolone; cell stiffness; metastasis
  9. Cytokine Growth Factor Rev. 2023 May 14. pii: S1359-6101(23)00021-7. [Epub ahead of print]
      In order to adapt to a higher proliferative rate and an increased demand for energy sources, cancer cells rewire their metabolic pathways, a process currently recognized as a hallmark of cancer. Even though the metabolism of glucose is perhaps the most discussed metabolic shift in cancer, lipid metabolic alterations have been recently recognized as relevant players in the growth and proliferation of cancer cells. Importantly, some of these metabolic alterations are reported to induce a drug resistant phenotype in cancer cells. The acquisition of drug resistance traits severely hinders cancer treatment, being currently considered one of the major challenges of the oncological field. Evidence suggests that Extracellular Vesicles (EVs), which play a crucial role in intercellular communication, may act as facilitators of tumour progression, survival and drug resistance by modulating several aspects involved in the metabolism of cancer cells. This review aims to gather and discuss relevant data regarding metabolic reprograming in cancer, particularly involving the glycolytic and lipid alterations, focusing on its influence on drug resistance and highlighting the relevance of EVs as intercellular mediators of this process.
    Keywords:  Cancer; Drug Resistance; Extracellular Vesicles; Intercellular Communication; Metabolic Reprogramming
  10. Chin Med J (Engl). 2023 May 26.
      BACKGROUND: Hepatic ischemia-reperfusion injury (HIRI) remains a common complication during liver transplantation (LT) in patients. As a key downstream effector of the Hippo pathway, Yes-associated protein (YAP) has been reported to be involved in various physiological and pathological processes. However, it remains elusive whether and how YAP may control autophagy activation during ischemia-reperfusion.METHODS: Human liver tissues from patients who had undergone LT were obtained to evaluate the correlation between YAP and autophagy activation. Both an in vitro hepatocyte cell line and in vivo liver-specific YAP knockdown mice were used to establish the hepatic ischemia-reperfusion models to determine the role of YAP in the activation of autophagy and the mechanism of regulation.
    RESULTS: Autophagy was activated in the post-perfusion liver grafts during LT in patients, and the expression of YAP positively correlated with the autophagic level of hepatocytes. Liver-specific knockdown of YAP inhibited hepatocytes autophagy upon hypoxia-reoxygenation and HIRI (P <0.05). YAP deficiency aggravated HIRI by promoting the apoptosis of hepatocytes both in the in vitro and in vivo models (P <0.05). Attenuated HIRI by overexpression of YAP was diminished after the inhibition of autophagy with 3-methyladenine. In addition, inhibiting autophagy activation by YAP knockdown exacerbated mitochondrial damage through increasing reactive oxygen species (P <0.05). Moreover, the regulation of autophagy by YAP during HIRI was mediated by AP1 (c-Jun) N-terminal kinase (JNK) signaling through binding to the transcriptional enhanced associate domain (TEAD).
    CONCLUSIONS: YAP protects against HIRI by inducing autophagy via JNK signaling that suppresses the apoptosis of hepatocytes. Targeting Hippo (YAP)-JNK-autophagy axis may provide a novel strategy for the prevention and treatment of HIRI.
  11. iScience. 2023 Jun 16. 26(6): 106754
      Hepatocellular carcinoma (HCC) is highly heterogeneous, and stemness signatures are frequently elevated in HCC tumor cells to generate heterogeneous subtypes via multidirectional differentiation. However, the mechanisms affecting the regulation of stemness in HCC remain unclear. In this study, we identified that lysosome-associated protein transmembrane-4β (LAPTM4B) was significantly overexpressed in stem-like tumor cell populations with multidirectional differentiation potential at the single cell level, and verified that LAPTM4B was closely related to stemness of HCC using in vitro and in vivo experiments. Mechanistically, elevated LAPTM4B suppresses Yes-associated protein (YAP) phosphorylation and ubiquitination degradation. In turn, stabilized YAP localizes to the nucleus and binds to cAMP responsive element binding protein-1 (CREB1), which promotes transcription of LAPTM4B. Overall, our findings suggest that LAPTM4B forms a positive feedback loop with YAP, which maintains the stemness of HCC tumor cells and leads to an unfavorable prognosis for HCC patients.
    Keywords:  Cancer; Cancer systems biology; Cell biology; Stem cells research
  12. Prog Mol Biol Transl Sci. 2023 ;pii: S1877-1173(23)00056-X. [Epub ahead of print]198 119-152
      Histone Deacetylases (HDACs) deacetylate lysine residues in histone and non-histone proteins. HDACs have been implicated in several diseases, including cancer, neurodegeneration, and cardiovascular disease. HDACs play an essential role in gene transcription, cell survival, growth, and proliferation, with histone hypoacetylation as one of the critical downstream signatures. HDAC inhibitors (HDACi) regulate gene expression epigenetically by restoring acetylation levels. Contrarily, only few HDACi have received FDA approval, and the majority are presently undergoing clinical trials to ascertain their effectiveness in the prevention and treatment of disease. In this book chapter, we give a detailed list of HDAC classes, and their functions in advancing diseases like cancer, cardiovascular, and neurodegeneration. Furthermore we touch upon novel and promising HDACi therapy approaches in the relevance of the current clinical scenario.
    Keywords:  Cancer; Cardiovascular; HDACi; HDACs; Neurodegeneration
  13. Protein Pept Lett. 2023 May 19.
      AIMS: Investigation of the molecular mechanism of tripartite motif 21 (TRIM21) in osteosarcoma (OS) would shed light on the understanding of the pathogenesis of OS.BACKGROUND: OS is the most frequent malignant bone tumor with a poor prognosis. TRIM21 has been reported to play a critical role in OS by regulating the expression of the TXNIP/p21 axis and inhibiting the senescence of OS cells.
    OBJECTIVE: This study aimed to explore the mechanism regulating the protein stability of TRIM21 in the process of OS senescence.
    METHODS: Human U2 OS cells were used to establish stable cells overexpressing TRIM21 (induced by Dox) or knocking down TRIM21. The co-immunoprecipitation (co-IP) assay was used to examine the interaction between TRIM21 and HSP90. Immunofluorescence (IF) assay was used to observe colocalization in OS cells. Western blot analysis was applied to detect the protein expression, and quantitative real-time PCR (qRT-PCR) assay was used to test the mRNA expression of corresponding genes. SA-β-gal staining was used to evaluate OS senescence.
    RESULTS: In this study, we verified the interaction between HSP90 and TRIM21 using a co-IP assay. Knockdown or inhibition of HSP90 with its inhibitor 17-AAG accelerated the degradation of TRIM21 by the proteasome in OS cells. CHIP E3 ligase mediated this degradation of TRIM21, with the knockdown of CHIP rescuing the downregulation of TRIM21 induced by 17-AAG. TRIM21 inhibited OS senescence and downregulated the expression of senescence marker p21, while CHIP exhibited an opposite regulatory role on p21 expression.
    CONCLUSION: Taken together, our results demonstrated that HSP90 is responsible for the stabilization of TRIM21 in OS and that the CHIP/TRIM21/p21 axis controlled by HSP90 affects the senescence of OS cells.
    Keywords:  CHIP; HSP90; TRIM21; osteosarcoma; p21; senescence
  14. Elife. 2023 May 23. pii: e80653. [Epub ahead of print]12
      The shape and size of the human cell nucleus is highly variable amongst cell types and tissues. Changes in nuclear morphology are associated with disease, including cancer, as well as with premature and normal aging. Despite the very fundamental nature of nuclear morphology, the cellular factors that determine nuclear shape and size are not well understood. To identify regulators of nuclear architecture in a systematic and unbiased fashion, we performed a high-throughput imaging-based siRNA screen targeting 867 nuclear proteins including chromatin-associated proteins, epigenetic regulators, and nuclear envelope components. Using multiple morphometric parameters and eliminating cell cycle effectors, we identified a set of novel determinants of nuclear size and shape. Interestingly, most identified factors altered nuclear morphology without affecting the levels of lamin proteins, which are known prominent regulators of nuclear shape. In contrast, a major group of nuclear shape regulators were modifiers of repressive heterochromatin. Biochemical and molecular analysis uncovered a direct physical interaction of histone H3 with lamin A mediated via combinatorial histone modifications. Furthermore, disease-causing lamin A mutations that result in disruption of nuclear shape inhibited lamin A-histone H3 interactions. Finally, oncogenic histone H3.3 mutants defective for H3K27 methylation resulted in nuclear morphology abnormalities. Altogether, our results represent a systematic exploration of cellular factors involved in determining nuclear morphology and they identify the interaction of lamin A with histone H3 as an important contributor to nuclear morphology in human cells.
    Keywords:  cell biology; chromosomes; gene expression; human
  15. Methods Mol Biol. 2023 ;2655 171-181
      Advanced microscopy techniques (such as STORM, STED, and SIM) have recently allowed the visualization of biological samples beyond the diffraction limit of light. Thanks to this breakthrough, the organization of molecules can be revealed within single cells as never before.Here, we describe the application of STochastic Optical Reconstruction Microscopy (STORM) for the study of polycomb group of proteins (PcG) in the context of chromatin organization. We present a clustering algorithm to quantitatively analyze the spatial distribution of nuclear molecules (e.g., EZH2 or its associated chromatin mark H3K27me3) imaged by 2D STORM. This distance-based analysis uses x-y coordinates of STORM localizations to group them into "clusters." Clusters are classified as singles if isolated or into islands if they form a group of closely associated clusters. For each cluster, the algorithm calculates the number of localizations, the area, and the distance to the closest cluster.This approach can be used for every type of adherent cell line and allows the imaging of every protein for which an antibody is available. It represents a comprehensive strategy to visualize and quantify how PcG proteins and related histone marks organize in the nucleus at nanometric resolution.
    Keywords:  Antibodies; Chromatin; Cluster analysis; Histone modifications; Imaging; Microscopy; PcG; Polycomb; STORM; Super-resolution