bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒07‒10
thirteen papers selected by
Ankita Daiya
BITS Pilani

  1. Cancers (Basel). 2022 Jul 04. pii: 3270. [Epub ahead of print]14(13):
      Epigenetic modifications are crucial for chromatin remodeling and transcriptional regulation. Post-translational modifications of histones are epigenetic processes that are fine-tuned by writer and eraser enzymes, and the disorganization of these enzymes alters the cellular state, resulting in human diseases. The KDM5 family is an enzymatic family that removes di- and tri-methyl groups (me2 and me3) from lysine 4 of histone H3 (H3K4), and its dysregulation has been implicated in cancer. Although H3K4me3 is an active chromatin marker, KDM5 proteins serve as not only transcriptional repressors but also transcriptional activators in a demethylase-dependent or -independent manner in different contexts. Notably, KDM5 proteins regulate the H3K4 methylation cycle required for active transcription. Here, we review the recent findings regarding the mechanisms of transcriptional regulation mediated by KDM5 in various contexts, with a focus on cancer, and further shed light on the potential of targeting KDM5 for cancer therapy.
    Keywords:  KDM5; MYC; RNA polymerase II; cancer; epigenetic regulator; histone demethylase
  2. Front Oncol. 2022 ;12 894585
      Polycomb repressive complex 2 (PRC2) is a multisubunit histone-modifying enzyme complex that mediates methylation of histone H3 lysine 27 (H3K27). Trimethylated H3K27 (H3K27me3) is an epigenetic hallmark of gene silencing. PRC2 plays a crucial role in a plethora of fundamental biological processes, and PRC2 dysregulation has been repeatedly implicated in cancers and developmental disorders. Here, we review the current knowledge on mechanisms of cellular regulation of PRC2 function, particularly regarding H3K27 methylation and chromatin targeting. PRC2-related disease mechanisms are also discussed. The mode of action of PRC2 in gene regulation is summarized, which includes competition between H3K27 methylation and acetylation, crosstalk with transcription machinery, and formation of high-order chromatin structure. Recent progress in the structural biology of PRC2 is highlighted from the aspects of complex assembly, enzyme catalysis, and chromatin recruitment, which together provide valuable insights into PRC2 function in close-to-atomic detail. Future studies on the molecular function and structure of PRC2 in the context of native chromatin and in the presence of other regulators like RNAs will continue to deepen our understanding of the stability and plasticity of developmental transcriptional programs broadly impacted by PRC2.
    Keywords:  PRC2; cancer; chromatin; developmental disorder; gene regulation; histone methylation; polycomb-group proteins; protein structure
  3. Front Med (Lausanne). 2022 ;9 892593
      Background: Alterations of epigenetic modification patterns are potential markers of cancer. The current study characterized six histone modifications in osteosarcoma and identified epigenetically dysregulated long non-coding RNAs (epi-lncRNAs).Methods: Multi-omics data were obtained from osteosarcoma cell line SJSA1 and a normal cell line. Differentially expressed lncRNAs (DElncRNAs) between osteosarcoma and normal skeletal muscle were analyzed using Limma. MACS2 was applied to identify the "peaks" modified by each histone in the cell. Promoters or enhancers of DElncRNA were overlapped with differential histone-modified regions (DHMR) to screen epi-lncRNAs. Univariate and multivariate Cox regression analysis were performed to detect the genes closely related to the prognosis of osteosarcoma and to construct risk models.
    Results: A total of 17 symbolic epi-lncRNA in osteosarcoma were screened, and 13 of them were differentially expressed between osteosarcoma and normal samples. Eight epi-lncRNAs were retained by Univariate Cox regression analysis. Four of these epi-lncRNAs were used to construct an epi-lncRNA signature. The risk score of each osteosarcoma sample in the high- or low-risk group was estimated according to the epi-lncRNA signature. The overall survival (OS) of the low-risk group was significantly better than that of the high-risk group. The area under the receiver operating characteristic (ROC) curve of the model was 0.79 and 0.82 for 1-, 3-, and 5-year OS, respectively.
    Conclusion: Our results revealed the histone modification pattern in osteosarcoma and developed 4-epi-lncRNA signature to predict the prognosis of osteosarcoma, laying a foundation for the identification of highly specific epigenetic biomarkers for osteosarcoma.
    Keywords:  histone modification; long non-coding RNAs; multiomics; osteosarcoma; prognosis
  4. C R Biol. 2022 May 11. 345(1): 11-16
      Cancer evolution was long-reduced to a genetic equation. The latest technological and subsequent conceptual advances, catalyzed by single-cell approaches, now begin to reveal the long-suspected part played by epigenomic and transcriptomic mechanisms in cancer evolution. Lie ahead numerous challenges to integrate multi-modal measurements of individual cancer cells over time and space, while aiming for better disease management and the discovery of therapeutic targets and biomarkers.
    Keywords:  Cancer; DNA methylation; Epigenomics; Histone modifications; Single-cell approaches
  5. Trends Genet. 2022 Jul 05. pii: S0168-9525(22)00148-2. [Epub ahead of print]
      The heterogeneity of transcriptional regulations by super-enhancers (SEs) is poorly understood in human cancers. Herein, we summarize a bioinformatics workflow for genome-wide SE profiling and identification of subtype-specific SEs and regulatory networks. Dissecting SE heterogeneity provides new insights into cancer biology and alternative therapeutic strategies for cancer precision medicine.
    Keywords:  cancer subtype; heterogeneity; multi-omics; regulatory network; super-enhancer; transcription regulation
  6. Clin Transl Oncol. 2022 Jul 06.
      Osteosarcoma (OS) is a common and malignant form of bone cancer, which affects children and young adults. OS is identified by osteogenic differentiation and metastasis. However, the exact molecular mechanism of OS development and progression is still unclear. Recently, long non-coding RNAs (lncRNA) have been proven to regulate OS proliferation and drug resistance. LncRNAs are longer than 200 nucleotides that represent the extensive applications in the processing of pre-mRNA and the pathogenesis of human diseases. Metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) is a well-known lncRNA known as a transcriptional and translational regulator. The aberrant expression of MALAT1 has been shown in several human cancers. The high level of MALAT1 is involved in OS cell growth and tumorigenicity by targeting several signaling pathways and miRNAs. Hence, MALAT1 might be a suitable approach for OS diagnosis and treatment. In this review, we will summarize the role of lncRNA MALAT1 in the pathophysiology of OS.
    Keywords:  Long non-coding RNAs; MALAT1; Osteosarcoma; Signaling pathways; miRNAs
  7. Crit Rev Oncol Hematol. 2022 Jul 02. pii: S1040-8428(22)00176-7. [Epub ahead of print]176 103752
      Acetylation is a reversible post-translational modification (PTM) that regulates important cellular processes such as proliferation, DNA damage repair and cell cycle progress. When the balance is broken, these processes are affected and lead to carcinogenesis. Therefore, the study of acetylation has led to its proposal as a target pathway for anticancer therapies. Here, we discuss how acetylation regulates the cell cycle process, how it is modified in cancer cells and which are the key proteins in the regulation of apoptosis induction in cancer cells that can become targets to fight cancer. The inhibition of acetylation has been proposed as an emergent therapy against cancer, compounds such as 6-Penthadecyl salicylic acid, Curcumin, Garcinol and C646, among others, are currently studied because they show antitumor activity related to the inhibition of acetylation. Recently, the use of the acetylomics research tool has improved the study of acetylation as a target against tumor cells, but still the thresholds between promoting DNA instability and regulating gene expression by acetylation are not clear in many cell types.
    Keywords:  Acetylation; Cancer; Cell cycle; Histone acetyltransferases; Post-translational modifications
  8. Natl Sci Rev. 2022 Jun;9(6): nwab230
      Cell plasticity endows differentiated cells with competence to be reprogrammed to other lineages. Although extrinsic factors driving cell-identity conversion have been extensively characterized, it remains elusive which intrinsic epigenetic attributes, including high-order chromatin organization, delineate cell plasticity. By analysing the transcription-factor-induced transdifferentiation from fibroblasts to hepatocytes, we uncovered contiguous compartment-switchable regions (CSRs) as a unique chromatin unit. Specifically, compartment B-to-A CSRs, enriched with hepatic genes, possessed a mosaic status of inactive chromatin and pre-existing and continuous accessibility in fibroblasts. Pre-existing accessibility enhanced the binding of inducible factor Foxa3, which triggered epigenetic activation and chromatin interaction as well as hepatic gene expression. Notably, these changes were restrained within B-to-A CSR boundaries that were defined by CTCF occupancy. Moreover, such chromatin organization and mosaic status were detectable in different cell types and involved in multiple reprogramming processes, suggesting an intrinsic chromatin attribute in understanding cell plasticity.
    Keywords:  cell plasticity; compartment-switchable regions; hepatic transdifferentiation; intrinsic properties; mosaic status; pre-existing accessibility
  9. J Cell Sci. 2022 Jul 01. pii: jcs259594. [Epub ahead of print]135(13):
      Nuclear speckles are dynamic membraneless bodies located in the cell nucleus. They harbor RNAs and proteins, many of which are splicing factors, that together display complex biophysical properties dictating nuclear speckle formation and maintenance. Although these nuclear bodies were discovered decades ago, only recently has in-depth genomic analysis begun to unravel their essential functions in modulation of gene activity. Major advancements in genomic mapping techniques combined with microscopy approaches have enabled insights into the roles nuclear speckles may play in enhancing gene expression, and how gene positioning to specific nuclear landmarks can regulate gene expression and RNA processing. Some studies have drawn a link between nuclear speckles and disease. Certain maladies either involve nuclear speckles directly or dictate the localization and reorganization of many nuclear speckle factors. This is most striking during viral infection, as viruses alter the entire nuclear architecture and highjack host machinery. As discussed in this Review, nuclear speckles represent a fascinating target of study not only to reveal the links between gene positioning, genome subcompartments and gene activity, but also as a potential target for therapeutics.
    Keywords:  Nuclear bodies; Nuclear organization; Nuclear speckles; Splicing factors
  10. Genes Dis. 2022 May;9(3): 741-752
      Osteosarcoma is the most common malignant bone tumour, and the metastasis of osteosarcoma is an important cause of death. Evidence has shown that the mevalonate pathway is highly activated and is expected to be a new target for tumour therapy. In this study, we investigated the effect of mevalonate signalling on osteosarcoma metastasis and its molecular mechanism. First, we found that the key rate-limiting enzyme of mevalonate signalling, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), was highly expressed in osteosarcoma cells, and inhibition of HMGCR with simvastatin significantly inhibited the motility of 143B cells. Next, we found that YAP1 activity was significantly upregulated in osteosarcoma cells and that YAP1 knockdown inhibited the motility of 143B cells. We also found that the mevalonate pathway regulated the motility of 143B cells by modulating YAP1 phosphorylation and cellular localization. Moreover, we found that the activity of YAP1 was regulated by the mevalonate pathway by modulating the cell membrane localization of RhoA. Finally, we demonstrated that inhibition of the mevalonate pathway notably reduced the lung metastasis of 143B cells, as reflected by the decreased incidence and number of metastatic nodules and the increased survival time of the nude mice. Taken together, our findings suggest that the mevalonate pathway can promote the metastasis of osteosarcoma by activating YAP1 via RhoA. Inhibition of the mevalonate pathway may be a promising therapeutic strategy for osteosarcoma metastasis.
    Keywords:  Metastasis; Mevalonate pathway; Osteosarcoma; RhoA; YAP1
  11. Sci China Life Sci. 2022 Jun 30.
      Multi-cellular organisms such as humans contain hundreds of cell types that share the same genetic information (DNA sequences), and yet have different cellular traits and functions. While how genetic information is passed through generations has been extensively characterized, it remains largely obscure how epigenetic information encoded by chromatin regulates the passage of certain traits, gene expression states and cell identity during mitotic cell divisions, and even through meiosis. In this review, we will summarize the recent advances on molecular mechanisms of epigenetic inheritance, discuss the potential impacts of epigenetic inheritance during normal development and in some disease conditions, and outline future research directions for this challenging, but exciting field.
    Keywords:  DNA methylation; DNA replication; epigenetic inheritance; histone deposition; histone modification
  12. Front Cell Dev Biol. 2022 ;10 905927
      Vascular cells are constantly subjected to physical forces associated with the rhythmic activities of the heart, which combined with the individual geometry of vessels further imposes oscillatory, turbulent, or laminar shear stresses on vascular cells. These hemodynamic forces play an important role in regulating the transcriptional program and phenotype of endothelial and smooth muscle cells in different regions of the vascular tree. Within the aorta, the lesser curvature of the arch is characterized by disturbed, oscillatory flow. There, endothelial cells become activated, adopting pro-inflammatory and athero-prone phenotypes. This contrasts the descending aorta where flow is laminar and endothelial cells maintain a quiescent and atheroprotective phenotype. While still unclear, the specific mechanisms involved in mechanosensing flow patterns and their molecular mechanotransduction directly impact the nucleus with consequences to transcriptional and epigenetic states. The linker of nucleoskeleton and cytoskeleton (LINC) protein complex transmits both internal and external forces, including shear stress, through the cytoskeleton to the nucleus. These forces can ultimately lead to changes in nuclear integrity, chromatin organization, and gene expression that significantly impact emergence of pathology such as the high incidence of atherosclerosis in progeria. Therefore, there is strong motivation to understand how endothelial nuclei can sense and respond to physical signals and how abnormal responses to mechanical cues can lead to disease. Here, we review the evidence for a critical role of the nucleus as a mechanosensor and the importance of maintaining nuclear integrity in response to continuous biophysical forces, specifically shear stress, for proper vascular function and stability.
    Keywords:  LINC complex; cytoskeleton; endothelial; mechanotransduction; nucleus; shear stress (fluid)
  13. Trends Biochem Sci. 2022 Jul 04. pii: S0968-0004(22)00143-8. [Epub ahead of print]
      The nucleosome-remodeling and deacetylase (NuRD) complex is an essential transcriptional regulator in all complex animals. All seven core subunits of the complex exist as multiple paralogs, raising the question of whether the complex might utilize paralog switching to achieve cell type-specific functions. We examine the evidence for this idea, making use of published quantitative proteomic data to dissect NuRD composition in 20 different tissues, as well as a large-scale CRISPR knockout screen carried out in >1000 human cancer cell lines. These data, together with recent reports, provide strong support for the idea that distinct permutations of the NuRD complex with tailored functions might regulate tissue-specific gene expression programs.
    Keywords:  NuRD complex; chromatin remodeling; paralog switching; transcriptional regulation