bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒08‒28
sixteen papers selected by
Ankita Daiya
BITS Pilani

  1. Eur J Pharmacol. 2022 Aug 18. pii: S0014-2999(22)00477-0. [Epub ahead of print] 175216
      Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and cancers. Acetylation is one of the most common post-translational modifications of proteins, and the acetylation levels are controlled by two mutually antagonistic enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HATs loosen the chromatin structure by neutralizing the positive charge of lysine residues of histones; whereas HDACs deacetylate certain histones, thus inhibiting gene transcription. Compared with HATs, HDACs have been more intensively studied, particularly regarding their clinical significance. HDACs extensively participate in the regulation of proliferation, migration, angiogenesis, immune escape, and therapeutic resistance of cancer cells, thus emerging as critical targets for clinical cancer therapy. Compared to HATs, inhibitors of HDAC have been clinically used for cancer treatment. Here, we enumerate and integratethe mechanisms of HDAC family members in tumorigenesis and cancer progression, and address the new and exciting therapeutic implications of single or combined HDAC inhibitor (HDACi) treatment.
    Keywords:  Acetylation; Cancer; Epigenetic modification; HDACis; HDACs
  2. Nat Rev Mol Cell Biol. 2022 Aug 26.
      Cells differentiate and progress through development guided by a dynamic chromatin landscape that mediates gene expression programmes. During development, mammalian cells display a paradoxical chromatin state: histone modifications associated with gene activation (trimethylated histone H3 Lys4 (H3K4me3)) and with gene repression (trimethylated H3 Lys27 (H3K27me3)) co-occur at promoters of developmental genes. This bivalent chromatin modification state is thought to poise important regulatory genes for expression or repression during cell-lineage specification. In this Review, we discuss recent work that has expanded our understanding of the molecular basis of bivalent chromatin and its contributions to mammalian development. We describe the factors that establish bivalency, especially histone-lysine N-methyltransferase 2B (KMT2B) and Polycomb repressive complex 2 (PRC2), and consider evidence indicating that PRC1 shapes bivalency and may contribute to its transmission between generations. We posit that bivalency is a key feature of germline and embryonic stem cells, as well as other types of stem and progenitor cells. Finally, we discuss the relevance of bivalent chromtin to human development and cancer, and outline avenues of future research.
  3. Cancers (Basel). 2022 Aug 22. pii: 4050. [Epub ahead of print]14(16):
      Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1-a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.
    Keywords:  chromatin kinase; lysine acetylase; lysine deacetylase; lysine demethylase; lysine methylase
  4. Nucleic Acids Res. 2022 Aug 26. pii: gkac702. [Epub ahead of print]
      In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of 'reader-writer' enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader-writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of γH2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.
  5. Int J Mol Sci. 2022 Aug 12. pii: 8988. [Epub ahead of print]23(16):
      Epigenetic modifications of histones (methylation, acetylation, phosphorylation, etc.) are of great importance in determining the functional state of chromatin. Changes in epigenome underlay all basic biological processes, such as cell division, differentiation, aging, and cancerous transformation. Post-translational histone modifications are mainly studied by immunoprecipitation with high-throughput sequencing (ChIP-Seq). It enables an accurate profiling of target modifications along the genome, but suffers from the high cost of analysis and the inability to work with living cells. Fluorescence microscopy represents an attractive complementary approach to characterize epigenetics. It can be applied to both live and fixed cells, easily compatible with high-throughput screening, and provide access to rich spatial information down to the single cell level. In this review, we discuss various fluorescent probes for histone modification detection. Various types of live-cell imaging epigenetic sensors suitable for conventional as well as super-resolution fluorescence microscopy are described. We also focus on problems and future perspectives in the development of fluorescent probes for epigenetics.
    Keywords:  epigenetics; fluorescent proteins; genetically encoded probes; histone modification
  6. Hum Mol Genet. 2022 Aug 26. pii: ddac204. [Epub ahead of print]
      Enhancers are pivotal for regulating gene transcription that occurs at promoters. Identification of the interacting enhancer-promoter pairs and understanding the mechanisms behind how they interact and how enhancers modulate transcription can provide fundamental insight into gene regulatory networks. Recently, advances in high-throughput methods in three major areas-chromosome conformation capture assay, such as Hi-C to study basic chromatin architecture, ectopic reporter experiments such as STARR-seq to quantify promoter and enhancer activity, and endogenous perturbations such as CRISPRi to identify enhancer-promoter compatibility-have further our knowledge about transcription. In this review, we will discuss the major method developments and key findings from these assays.
  7. Front Pharmacol. 2022 ;13 934843
      Cancer expands clonally, capitalizing on the variations between growing cells. Cancer cells specialize in one or more functions to gain an advantage. This study examined the prediction that cells would be vulnerable to drugs that perturb their specific tasks. We analyzed the correlation between gene expression and the response to drug perturbations in different cancer cells. Next, we assigned every cancer cell to an archetype based on gene expression. Finally, we calculated the enrichment of the cancer hallmark gene sets in each cell, archetypes, and response to drug treatment. We found that the extremes of gene expression were susceptible to change in response to perturbations. This correlation predicted the growth rate inhibition of breast cancer cells. Cancer hallmarks were enriched differently in the archetypes, and this enrichment predicted the cell's response to perturbations. We present evidence that specialized cancer cells are sensitive to compounds that perturb their tasks.
    Keywords:  archetype analysis; cancer hallmarks; drug perturbations; gene expression; task specialization
  8. Data Brief. 2022 Oct;44 108506
      The data presented in this article is related to a rapid communication entitled "β-arrestin 2 suppresses the activation of YAP by promoting LATS kinase activity". This article describes the correlation of β-arrestin 2 and YAP phosphorylation in patient-derived organoid models. Here, we analyzed 45 colon cancer organoids (CCOs) selected in the related research article to investigate the role of β-arrestin 2 in YAP phosphorylation. Hematoxylin and eosin (H&E) staining and immunohistochemistry data showed that the CCOs maintained tissue architecture and histological features of their original cancer tissues. Moreover, mutation data detected from RNA-seq (RNA-sequencing) analysis showed that these CCOs retained the genetic features of their original colon cancer tissues as well. We also confirmed at the protein level that organoids expressing β-arrestin 2 showed high expression of phosphorylated YAP. These organoid model studies strongly support the related research article that β-arrestin 2 suppresses the activation of YAP in colon cancer.
    Keywords:  Cancer organoid; Hippo pathway; Patient-derived model; Yes-associated protein (YAP); β-arrestin 2
  9. Nat Commun. 2022 Aug 23. 13(1): 4941
      Physiologic laminar shear stress (LSS) induces an endothelial gene expression profile that is vasculo-protective. In this report, we delineate how LSS mediates changes in the epigenetic landscape to promote this beneficial response. We show that under LSS, KLF4 interacts with the SWI/SNF nucleosome remodeling complex to increase accessibility at enhancer sites that promote the expression of homeostatic endothelial genes. By combining molecular and computational approaches we discover enhancers that loop to promoters of KLF4- and LSS-responsive genes that stabilize endothelial cells and suppress inflammation, such as BMPR2, SMAD5, and DUSP5. By linking enhancers to genes that they regulate under physiologic LSS, our work establishes a foundation for interpreting how non-coding DNA variants in these regions might disrupt protective gene expression to influence vascular disease.
  10. Transl Oncol. 2022 Aug 21. pii: S1936-5233(22)00158-9. [Epub ahead of print]25 101499
      BACKGROUND: Osteosarcoma (OS) is a common malignant tumor in osteoarticular system, the 5-year overall survival of which is poor. Enhancer RNAs (eRNAs) have been implicated in the tumorigenesis of various cancer types, whereas their roles in OS tumorigenesis remains largely unclear.METHODS: Differentially expressed eRNAs (DEEs), transcription factors (DETFs), target genes (DETGs) were identified using limma (Linear Models for Microarray Analysis) package. Prognosis-related DEEs were accessed by univariate Cox regression analysis. A multivariate model was constructed to evaluate the prognosis of OS samples. Prognosis-related DEEs, DETFs, DETGs, immune cells, and hallmark gene sets were co-analyzed to construct an regulatory network. Specific inhibitors were also filtered by connectivity Map analysis. External validation and scRNA-seq analysis were performed to verify our key findings.
    RESULTS: 3,981 DETGs, 468 DEEs, 51 DETFs, and 27 differentially expressed hallmark gene sets were identified. A total of Multivariate risk predicting model based on 18 prognosis-related DEEs showed a high accuracy (area under curve (AUC) = 0.896). GW-8510 was the candidate inhibitor targeting prognosis-related DEEs (mean = 0.670, p < 0.001). Based on the OS tumorigenesis-related regulation network, we identified that CCAAT enhancer binding protein alpha (CEBPA, DETF) may regulate CD8A molecule (CD8A, DEE), thereby promoting the transcription of CD3E molecule (CD3E, DETG), which may affect allograft rejection based on CD8+ T cells.
    CONCLUSION: We constructed an eRNA-based prognostic model for predicting the OS patients' prognosis and explored the potential regulation network for OS tumorigenesis by an integrated bioinformatics analysis, providing promising therapeutic targets for OS patients.
    Keywords:  CD3E; CD8A; CEBPA; Network; Osteosarcoma; eRNA
  11. Nat Commun. 2022 Aug 25. 13(1): 4995
      Dysregulation of Hippo pathway leads to hyperactivation of YAP-TEAD transcriptional complex in various cancers, including colorectal cancer (CRC). In this study, we observed that HHEX (Hematopoietically expressed homeobox) may enhance transcription activity of the YAP-TEAD complex. HHEX associates with and stabilizes the YAP-TEAD complex on the regulatory genomic loci to coregulate the expression of a group of YAP/TEAD target genes. Also, HHEX may indirectly regulate these target genes by controlling YAP/TAZ expression. Importantly, HHEX is required for the pro-tumorigenic effects of YAP during CRC progression. In response to serum stimulation, CK2 (Casein Kinase 2) phosphorylates HHEX and enhances its interaction with TEAD4. A CK2 inhibitor CX-4945 diminishes the interaction between HHEX and TEAD4, leading to decreased expression of YAP/TEAD target genes. CX-4945 synergizes the antitumor activity of YAP-TEAD inhibitors verteporfin and Super-TDU. Elevated expression of HHEX is correlated with hyperactivation of YAP/TEAD and associated with poor prognosis of CRC patients. Overall, our study identifies HHEX as a positive modulator of YAP/TEAD to promote colorectal tumorigenesis, providing a new therapeutic strategy for targeting YAP/TEAD in CRC.
  12. Front Mol Biosci. 2022 ;9 930223
      Autophagy is an evolutionary conserved catabolic pathway that uses a unique double-membrane vesicle, called autophagosome, to sequester cytosolic components, deliver them to lysosomes and recycle amino-acids. Essentially, autophagy acts as a cellular cleaning system that maintains metabolic balance under basal conditions and helps to ensure nutrient viability under stress conditions. It is also an important quality control mechanism that removes misfolded or aggregated proteins and mediates the turnover of damaged and obsolete organelles. In this regard, the idea that autophagy is a non-selective bulk process is outdated. It is now widely accepted that forms of selective autophagy are responsible for metabolic rewiring in response to cellular demand. Given its importance, autophagy plays an essential role during tumorigenesis as it sustains malignant cellular growth by acting as a coping-mechanisms for intracellular and environmental stress that occurs during malignant transformation. Cancer development is accompanied by the formation of a peculiar tumor microenvironment that is mainly characterized by hypoxia (oxygen < 2%) and low nutrient availability. Such conditions challenge cancer cells that must adapt their metabolism to survive. Here we review the regulation of autophagy and selective autophagy by hypoxia and the crosstalk with other stress response mechanisms, such as UPR. Finally, we discuss the emerging role of ER-phagy in sustaining cellular remodeling and quality control during stress conditions that drive tumorigenesis.
    Keywords:  ER stress; ER-phagy; UPR; autophagy; cancer; endoplasmic reticulum; hypoxia
  13. Front Genet. 2022 ;13 923737
      Background: The latest research identified cuproptosis as an entirely new mechanism of cell death. However, as a key regulator in copper-induced cell death, the prognostic and immunotherapeutic value of FDX1 in pan-cancer remains unclear. Methods: Data from the UCSC Xena, GEPIA, and CPTAC were analyzed to conduct an inquiry into the overall differential expression of FDX1 across multiple cancer types. The expression of FDX1 in GBM, LUAD and HCC cell lines as well as their control cell lines was verified by RT-QPCR. The survival prognosis, clinical features, and genetic changes of FDX1 were also evaluated. Finally, the relationship between FDX1 and immunotherapy response was further explored through Gene Set Enrichment Analysis enrichment analysis, tumor microenvironment, immune cell infiltration, immune gene co-expression and drug sensitivity analysis. Results: The transcription and protein expression of FDX1 were significantly reduced in most cancer types and had prognostic value for the survival of certain cancer patients such as ACC, KIRC, HNSC, THCA and LGG. In some cancer types, FDX1 expression was also markedly correlated with the clinical characteristics, TMB, MSI, and antitumor drug susceptibility or resistance of different tumors. Gene set enrichment analysis showed that FDX1 was significantly associated with immune-related pathways. Moreover, the expression level of FDX1 was confirmed to be strongly correlated with immune cell infiltration, immune checkpoint genes, and immune regulatory genes to a certain extent. Conclusion: This study comprehensively explored the potential value of FDX1 as a prognostic and immunotherapeutic marker for pan-cancer, providing new direction and evidence for cancer therapy.
    Keywords:  Fdx1; cuproptosis; drug resistance; immunotherapy; pan-cancer
  14. Biosci Rep. 2022 Aug 24. pii: BSR20221002. [Epub ahead of print]
      Worldwide, ovarian cancer (OC) is the seventh common cancer and the second most common cause of cancer death in women. Due to high rates of relapse, there is an urgent need for the identification of new targets for OC treatment. The far-upstream element binding protein 1 (FBP1) and enhancer of zeste homolog 2 (EZH2) are emerging proto-oncogenes that regulate cell proliferation and metastasis. In the present study, Oncomine data analysis demonstrated that FBP1 was closely associated with the development of OC, and The Cancer Genome Atlas (TCGA) data analysis indicated that there was a positive correlation between FBP1 and EZH2 in ovarian tissues. Moreover, we found that FBP1 knockdown suppressed tumor formation in nude mice and cisplatin resistance of OC cells, but the role of FBP1 in the cisplatin resistance of OC cells remained unclear. In addition, we verified physical binding between FBP1 and EZH2 in OC cells, and we demonstrated that FBP1 knockdown enhanced cisplatin cytotoxicity in OC cells and downregulated EZH2 expression and trimethylation of H3K27. These results suggested that FBP1 increases cisplatin resistance of OC cells by upregulating EZH2/H3K27me3. Thus, FBP1 is a prospective novel target for the development of OC treatment.
    Keywords:  EZH2; FBP1; H3K27me3; cisplatin resistance; clinical significance; ovarian cancer
  15. iScience. 2022 Aug 19. 25(8): 104827
      Triple-negative breast cancers (TNBCs) are frequently poorly differentiated with high propensity for metastasis. Enhancer of zeste homolog 2 (EZH2) is the lysine methyltransferase of polycomb repressive complex 2 that mediates transcriptional repression in normal cells and in cancer through H3K27me3. However, H3K27me3-independent non-canonical functions of EZH2 are incompletely understood. We reported that EZH2 phosphorylation at T367 by p38α induces TNBC metastasis in an H3K27me3-independent manner. Here, we show that cytosolic EZH2 methylates p38α at lysine 139 and 165 leading to enhanced p38α stability and that p38 methylation and activation require T367 phosphorylation of EZH2. Dual inhibition of EZH2 methyltransferase and p38 kinase activities downregulates pEZH2-T367, H3K27me3, and p-p38 pathways in vivo and reduces TNBC growth and metastasis. These data uncover a cooperation between EZH2 canonical and non-canonical mechanisms and suggest that inhibition of these pathways may be a potential therapeutic strategy.
    Keywords:  Cancer; Epigenetics; Molecular biology
  16. Cancer Lett. 2022 Aug 23. pii: S0304-3835(22)00352-4. [Epub ahead of print] 215868
      Pancreatic Ductal Adenocarcinoma (PDA) is one of the most lethal types of cancer with a dismal prognosis. KRAS mutation is a commonly identified oncogene in PDA tumorigenesis and P21-activated kinases (PAKs) are its downstream mediator. While PAK1 is more well-studied, PAK4 also attracted increasing interest. In PDA, PAK inhibition not only reduces cancer cell viability but also sensitizes it to chemotherapy. While PDA remains resistant to existing immunotherapies, PAK inhibition has been shown to increase cancer immunogenicity of melanoma, glioblastoma and PDA. Furthermore, autophagy plays an important role in PDA immune evasion, and accumulating evidence has pointed to a connection between PAK and cancer cell autophagy. In this literature review, we aim to summarize currently available studies that have assessed the potential connection between PAK, autophagy and immune evasion in PDA biology to guide future research.
    Keywords:  Autophagy; Immune evasion; P21 activated kinase; Pancreatic cancer