bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022‒06‒12
ten papers selected by
Ankita Daiya
BITS Pilani

  1. Cell Biosci. 2022 Jun 03. 12(1): 83
      Transcription factors directly regulate gene expression by recognizing and binding to specific DNA sequences, involving the dynamic alterations of chromatin structure and the formation of a complex with different kinds of cofactors, like DNA/histone modifying-enzymes, chromatin remodeling factors, and cell cycle factors. Despite the significance of transcription factors, it remains unclear to determine how these cofactors are regulated to cooperate with transcription factors, especially DNA/histone modifying-enzymes. It has been known that DNA/histone modifying-enzymes are regulated by post-translational modifications. And the most common and important modification is phosphorylation. Even though various DNA/histone modifying-enzymes have been classified and partly explained how phosphorylated sites of these enzymes function characteristically in recent studies. It still needs to find out the relationship between phosphorylation of these enzymes and the diseases-associated transcriptional regulation. Here this review describes how phosphorylation affects the transcription activity of these enzymes and other functions, including protein stability, subcellular localization, binding to chromatin, and interaction with other proteins.
    Keywords:  DNA/histone modifying-enzymes; Histone acetylation; Methylation; Phosphorylation; Transcription activity; Transcription factors
  2. Theranostics. 2022 ;12(9): 4269-4287
      The Hippo signaling pathway is an evolutionarily conserved network that regulates organ size and tissue homeostasis in mammals. This pathway controls various cell functions, such as growth, proliferation, survival, apoptosis, and stemness by switching 'on' or 'off' its inhibitory and/or transcriptional module, thereby regulating target gene(s) expression. Altered Hippo signaling has been implicated in various forms of cancers. Increasing evidence suggests cross-talk between the Hippo signaling pathway and non-coding RNAs, in particular circular RNAs (circRNAs). In this context, the current review presents the mechanistic interplay between the Hippo pathway and related circRNAs in various forms of cancers, along with the capabilities of these circRNAs to function either as tumor suppressors or oncogenes through miRNA sponging or protein binding mechanisms. Furthermore, we discuss the constraints and limitations in circRNA mechanistic studies while highlighting some outstanding questions regarding the roles of circRNAs associated with the Hippo-YAP pathway in cancer. Finally, we delineate the potential of these circRNAs to be employed as diagnostic and prognostic biomarkers, as well as molecular hotspots for cancer therapy.
    Keywords:  Hippo pathway; YAP; cancer progression; circRNA; circular RNA; signal transduction
  3. Gene. 2022 Jun 06. pii: S0378-1119(22)00459-0. [Epub ahead of print] 146640
      While enhancers in a particular tissue coordinately fulfill regulatory functions, these functions are heterogeneous in nature and comprise of multiple enhancer subclasses and the associated regulatory mechanisms. In this work, we used multiple cell lines to identify enhancer subclasses linked to development, differentiation, and cellular identity. We found that enhancer functional heterogeneity during development encompasses subclasses of ubiquitous functions (11%), development specific regulatory activity (62%), and chromatin interactions (12%). In differentiated cell lines, ubiquitous enhancers (10%) stay active across multiple cell lines.They are accompanied by a large enhancer subclass (ranging from 33% to 63%) with functions specific to the corresponding lineage. The remaining enhancers (27-40%) establish regulatory chromatin structure and facilitate interactions of cell type-specific enhancers with their target promoters. In addition to specialized functions of cell type-specific enhancers, we show that proper accounting of enhancer heterogeneity leads to a 10% increase in accuracy of enhancer classification, which significantly improves the modeling of enhancers and identification of underlying regulatory mechanisms. In summary, our observations suggest that although cell type-specific enhancers are heterogeneous and coordinate different regulatory programs, enhancers from different cell lines maintain common categories of functional groups across developmental and differentiation stages, indicating a higher order rule followed by enhancer-gene regulation.
  4. Bioessays. 2022 Jun 03. e2200043
      Eukaryotic genome DNA is wrapped around core histones and forms a nucleosome structure. Together with associated proteins and RNAs, these nucleosomes are organized three-dimensionally in the cell as chromatin. Emerging evidence demonstrates that chromatin consists of rather irregular and variable nucleosome arrangements without the regular fiber structure and that its dynamic behavior plays a critical role in regulating various genome functions. Single-nucleosome imaging is a promising method to investigate chromatin behavior in living cells. It reveals local chromatin motion, which reflects chromatin organization not observed in chemically fixed cells. The motion data is like a gold mine. Data analyses from many aspects bring us more and more information that contributes to better understanding of genome functions. In this review article, we describe imaging of single-nucleosomes and their tracked behavior through oblique illumination microscopy. We also discuss applications of this technique, especially in elucidating nucleolar organization in living cells.
    Keywords:  30-nm chromatin fiber; chromatin; chromatin dynamics; liquid-liquid phase separation; nucleolus; nucleosome; single-molecule imaging
  5. Int J Cancer. 2022 Jun 06.
      Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Co-targeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient-derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC.
    Keywords:  CRISPR/Cas9 screen; Colorectal cancer; EHMT2; HDAC inhibitor; synthetic lethality
  6. Cancer Cell Int. 2022 Jun 08. 22(1): 209
      Colorectal cancer (CRC) is the third cause of cancer death in the world that arises from the glandular and epithelial cells of the large intestine, during a series of genetic or epigenetic alternations. Recently, long non-coding RNAs (lncRNAs) has opened a separate window of research in molecular and translational medicine. Emerging evidence has supported that lncRNAs can regulate cell cycle of CRC cells. LncRNA NEAT1 has been verified to participate in colon cancer development and progression. NEAT1 as a competing endogenous RNA could suppress the expression of miRNAs, and then regulate molecules downstream of these miRNAs. In this review, we summarized emerging roles of NEAT1 in CRC cells.
    Keywords:  Colorectal cancer; NEAT1; Progression; lncRNAs
  7. Curr Opin Genet Dev. 2022 Jun 06. pii: S0959-437X(22)00033-8. [Epub ahead of print]75 101924
      Remarkable technological progress has led to breakthrough discoveries in epitranscriptomics, reshaping our understanding of modifications decorating RNA. The past decade has seen a tremendous endeavor to describe the nature, functions, and biological roles of messenger RNA (mRNA) modifications, positioning epitranscriptomics as a crucial pillar in tumor biology. Like DNA and histone modifications, mRNA marks have been increasingly linked to cancer pathogenesis. Here, we summarize the latest research in cancer epitranscriptomics with emphasis on N6-methyladenosine, untangling its contribution to five prime oncogenic features: tumor growth, activating invasion and metastasis, stemness, metabolic reprogramming, and tumor microenvironment. We discuss mRNA-modifying enzymes, their impact on biological processes, and contribution to cancer hallmarks. We spotlight epitranscriptomics as a promising bonanza for forthcoming targeting approaches in cancer therapy.
  8. Cureus. 2022 May;14(5): e24803
      In the last decade, there has been remarkable progress in research toward understanding and refining the hallmarks of cancer. In this review, we propose a new hallmark - "pro-survival autophagy." The importance of pro-survival autophagy is well established in tumorigenesis, as it is related to multiple steps in cancer progression and vital for some cancers. Autophagy is a potential anti-cancer therapeutic target. For this reason, autophagy is a good candidate as a new hallmark of cancer. We describe two enabling characteristics that play a major role in enabling cells to acquire the hallmarks of cancer - "tumor-promoting microenvironment and macroenvironment" and "cancer epigenetics, genome instability and mutation." We also discuss the recent updates, therapeutic and prognostic implications of the eight hallmarks of cancer described by Hanahan et al. in 2011. Understanding these hallmarks and enabling characteristics is key not only to developing new ways to treat cancer efficiently but also to exploring options to overcome cancer resistance to treatment.
    Keywords:  autophagy; cancer; genome instability; hallmark; macroenvironment; microenvironment; tumor
  9. Comput Struct Biotechnol J. 2022 ;20 2672-2679
      There is a growing need to build a model that uses single cell RNA-seq (scRNA-seq) to separate malignant cells from nonmalignant cells and to identify tumor of origin of single cells and/or circulating tumor cells (CTCs). Currently, it is infeasible to build a tumor of origin model learnt from scRNA-seq by machine learning (ML). We then wondered if an ML model learnt from bulk transcriptomes is applicable to scRNA-seq to infer single cells' tumor presence and further indicate their tumor of origin. We used k-nearest neighbors, one-versus-all support vector machine, one-versus-one support vector machine, random forest and introduced scTumorTrace to conduct a pioneering experiment containing leukocytes and seven major cancer types where bulk RNA-seq and scRNA-seq data were available. 13 ML models learnt from bulk RNA-seq were all reliable to use (F-score > 96%) shown by a validation set of bulk transcriptomes, but none of them was applicable to scRNA-seq except scTumorTrace. Making inferences from bulk RNA-seq to scRNA-seq was impaired by feature selection and improved by log2-transformed TPM units. scTumorTrace with transcriptome-wide 2-tuples showed F-score beyond 98.74 and 94.29% in inferring tumor presence and tumor of origin at single-cell resolution and correctly identified 45 single candidate prostate CTCs but lineage-confirmed non-CTCs as leukocytes. We concluded that modern ML techniques are quantitative and could hardly address the raised questions. scTumorTrace with transcriptome-wide 2-tuples is qualitative, standardization-free and not subject to log2-transformed quantities, enabling us to infer tumor presence of single cell transcriptomes and their tumor of origin from bulk transcriptomes.
    Keywords:  Circulating tumor cells; Digit medicine; RNA-seq; Single cell transcriptomes; Translational bioinformatics
  10. Cancers (Basel). 2022 May 31. pii: 2745. [Epub ahead of print]14(11):
      When a cell is damaged, it must decide how to respond. As a consequence of a variety of stresses, cells can induce well-regulated programmes such as senescence, a persistent proliferative arrest that limits their replication. Alternatively, regulated programmed cell death can be induced to remove the irreversibly damaged cells in a controlled manner. These programmes are mainly triggered and controlled by the tumour suppressor protein p53 and its complex network of effectors, but how it decides between these wildly different responses is not fully understood. This review focuses on the key proteins involved both in the regulation and induction of apoptosis and senescence to examine the key events that determine cell fate following damage. Furthermore, we examine how the regulation and activity of these proteins are altered during the progression of many chronic diseases, including cancer.
    Keywords:  BCL-2; apoptosis; p53; senescence