bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–11–13
fiveteen papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. The Regulation of the Hippo Pathway by Intercellular Junction Proteins.
  2. H3K27me3 in Diffuse Midline Glioma and Epithelial Ovarian Cancer: Opposing Epigenetic Changes Leading to the Same Poor Outcomes.
  3. Factors and Mechanisms That Influence Chromatin-Mediated Enhancer-Promoter Interactions and Transcriptional Regulation.
  4. Extrachromosomal DNA (ecDNA): an origin of tumor heterogeneity, genomic remodeling, and drug resistance.
  5. The LINC Complex Assists the Nuclear Import of Mechanosensitive Transcriptional Regulators.
  6. Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer.
  7. Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing.
  8. Drug Resistance in Cancers: A Free Pass for Bullying.
  9. Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death.
  10. Chromatin Dynamics During Entry to Quiescence and Compromised Functionality in Cancer Cells.
  11. Nuclear Organization in Response to Stress: A Special Focus on Nucleoli.
  12. Review on Advanced Cancer Modeling for a Cancer Study.
  13. Cellular Prion Protein Role in Cancer Biology: Is It A Potential Therapeutic Target?
  14. Nuclear Actin Dynamics in Gene Expression, DNA Repair, and Cancer.
  15. Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Function, and Phenotype.
  1. Life (Basel). 2022 Nov 05. pii: 1792. [Epub ahead of print]12(11):
    The Regulation of the Hippo Pathway by Intercellular Junction Proteins.
    Usama Sharif Ahmad, Jutamas Uttagomol, Hong Wan.
      The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species. The downstream effectors of this pathway, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are considered vital in promoting the output of the Hippo pathway, with activation of upstream kinases negatively regulating YAP/TAZ activity. The upstream regulation of the Hippo pathway is not entirely understood on a molecular level. However, several studies have shown that numerous cellular and non-cellular mechanisms such as cell polarity, contact inhibition, soluble factors, mechanical forces, and metabolism can convey external stimuli to the intracellular kinase cascade, promoting the activation of key components of the Hippo pathway and therefore regulating the subcellular localisation and protein activity of YAP/TAZ. This review will summarise what we have learnt about the role of intercellular junction-associated proteins in the activation of this pathway, including adherens junctions and tight junctions, and in particular our latest findings about the desmosomal components, including desmoglein-3 (DSG3), in the regulation of YAP signalling, phosphorylation, and subcellular translocation.
    Keywords:  Hippo pathway; TAZ; YAP; adherens junctions; cell–cell junctions; desmoglein-3; desmosomes; phosphorylated YAP; tight junctions
    DOI:  https://doi.org/10.3390/life12111792
  2. Cells. 2022 Oct 26. pii: 3376. [Epub ahead of print]11(21):
    H3K27me3 in Diffuse Midline Glioma and Epithelial Ovarian Cancer: Opposing Epigenetic Changes Leading to the Same Poor Outcomes.
    Charles A Day, Edward H Hinchcliffe, James P Robinson.
      Histone post-translational modifications modulate gene expression through epigenetic gene regulation. The core histone H3 family members, H3.1, H3.2, and H3.3, play a central role in epigenetics. H3 histones can acquire many post-translational modifications, including the trimethylation of H3K27 (H3K27me3), which represses transcription. Triple methylation of H3K27 is performed by the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2), a component of the Polycomb Repressive Complex 2. Both global increases and decreases in H3K27me3 have been implicated in a wide range of cancer types. Here, we explore how opposing changes in H3K27me3 contribute to cancer by highlighting its role in two vastly different cancer types; (1) a form of glioma known as diffuse midline glioma H3K27-altered and (2) epithelial ovarian cancer. These two cancers vary widely in the age of onset, sex, associated mutations, and cell and organ type. However, both diffuse midline glioma and ovarian cancer have dysregulation of H3K27 methylation, triggering changes to the cancer cell transcriptome. In diffuse midline glioma, the loss of H3K27 methylation is a primary driving factor in tumorigenesis that promotes glial cell stemness and silences tumor suppressor genes. Conversely, hypermethylation of H3K27 occurs in late-stage epithelial ovarian cancer, which promotes tumor vascularization and tumor cell migration. By using each cancer type as a case study, this review emphasizes the importance of H3K27me3 in cancer while demonstrating that the mechanisms of histone H3 modification and subsequent gene expression changes are not a one-size-fits-all across cancer types.
    Keywords:  EZH2; H3K27M; K3K27me3; PRC2; diffuse intrinsic pontine glioma; diffuse midline glioma; epigenetics; epithelial ovarian cancer; histone H3
    DOI:  https://doi.org/10.3390/cells11213376
  3. Cancers (Basel). 2022 Nov 02. pii: 5404. [Epub ahead of print]14(21):
    Factors and Mechanisms That Influence Chromatin-Mediated Enhancer-Promoter Interactions and Transcriptional Regulation.
    Shinsuke Ito, Nando Dulal Das, Takashi Umehara, Haruhiko Koseki.
      Eukaryotic gene expression is regulated through chromatin conformation, in which enhancers and promoters physically interact (E-P interactions). How such chromatin-mediated E-P interactions affect gene expression is not yet fully understood, but the roles of histone acetylation and methylation, pioneer transcription factors, and architectural proteins such as CCCTC binding factor (CTCF) and cohesin have recently attracted attention. Moreover, accumulated data suggest that E-P interactions are mechanistically involved in biophysical events, including liquid-liquid phase separation, and in biological events, including cancers. In this review, we discuss various mechanisms that regulate eukaryotic gene expression, focusing on emerging views regarding chromatin conformations that are involved in E-P interactions and factors that establish and maintain them.
    Keywords:  cancer; enhancer; gene expression; histone modifications; liquid–liquid phase separation; promoter
    DOI:  https://doi.org/10.3390/cancers14215404
  4. Biochem Soc Trans. 2022 Nov 10. pii: BST20221045. [Epub ahead of print]
    Extrachromosomal DNA (ecDNA): an origin of tumor heterogeneity, genomic remodeling, and drug resistance.
    Lauren T Pecorino, Roel G W Verhaak, Anton Henssen, Paul S Mischel.
      The genome of cancer cells contains circular extrachromosomal DNA (ecDNA) elements not found in normal cells. Analysis of clinical samples reveal they are common in most cancers and their presence indicates poor prognosis. They often contain enhancers and driver oncogenes that are highly expressed. The circular ecDNA topology leads to an open chromatin conformation and generates new gene regulatory interactions, including with distal enhancers. The absence of centromeres leads to random distribution of ecDNAs during cell division and genes encoded on them are transmitted in a non-mendelian manner. ecDNA can integrate into and exit from chromosomal DNA. The numbers of specific ecDNAs can change in response to treatment. This dynamic ability to remodel the cancer genome challenges long-standing fundamentals, providing new insights into tumor heterogeneity, cancer genome remodeling, and drug resistance.
    Keywords:  cancer genome; drug resistance; extrachromosomal DNA; genomic remodelling; oncogenes; tumor heterogeneity
    DOI:  https://doi.org/10.1042/BST20221045
  5. Results Probl Cell Differ. 2022 ;70 315-337
    The LINC Complex Assists the Nuclear Import of Mechanosensitive Transcriptional Regulators.
    Tomoyo Takata, Miki Matsumura.
      Mechanical forces play pivotal roles in directing cell functions and fate. To elicit gene expression, either intrinsic or extrinsic mechanical information are transmitted into the nucleus beyond the nuclear envelope via at least two distinct pathways, possibly more. The first and well-known pathway utilizes the canonical nuclear transport of mechanoresponsive transcriptional regulators through the nuclear pore complex, which is an exclusive route for macromolecular trafficking between the cytoplasm and nucleoplasm. The second pathway depends on the linker of the nucleoskeleton and cytoskeleton (LINC) complex, which is a molecular bridge traversing the nuclear envelope between the cytoskeleton and nucleoskeleton. This protein complex is a central component in mechanotransduction at the nuclear envelope that transmits mechanical information from the cytoskeleton into the nucleus to influence the nuclear structure, nuclear stiffness, chromatin organization, and gene expression. Besides the mechanical force transducing function, recent increasing evidence shows that the LINC complex plays a role in controlling nucleocytoplasmic transport of mechanoresponsive transcriptional regulators. Here we discuss recent findings regarding the contribution of the LINC complex to the regulation of intracellular localization of the most-notable mechanosensitive transcriptional regulators, β-catenin, YAP, and TAZ.
    Keywords:  Armadillo repeat; LINC complex; Mechanotransduction; NPC; Nesprin; Nuclear envelope; Nuclear pore complex; Nuclear trafficking; Nuclear transport; SUN; YAP; β-catenin
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_11
  6. Semin Cancer Biol. 2022 Nov 05. pii: S1044-579X(22)00216-4. [Epub ahead of print]
    Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer.
    Egle-Helene Ervin, Rhiannon French, Chao-Hui Chang, Siim Pauklin.
      Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
    Keywords:  Cancer; Cancer stem cell; Gene expression regulation; Stemness; Transcription factor
    DOI:  https://doi.org/10.1016/j.semcancer.2022.11.001
  7. EMBO Rep. 2022 Nov 10. e55345
    Paraspeckles interact with SWI/SNF subunit ARID1B to regulate transcription and splicing.
    Divya Reddy, Saikat Bhattacharya, Michaella Levy, Ying Zhang, Madelaine Gogol, Hua Li, Laurence Florens, Jerry L Workman.
      Paraspeckles are subnuclear RNA-protein structures that are implicated in important processes including cellular stress response, differentiation, and cancer progression. However, it is unclear how paraspeckles impart their physiological effect at the molecular level. Through biochemical analyses, we show that paraspeckles interact with the SWI/SNF chromatin-remodeling complex. This is specifically mediated by the direct interaction of the long-non-coding RNA NEAT1 of the paraspeckles with ARID1B of the cBAF-type SWI/SNF complex. Strikingly, ARID1B depletion, in addition to resulting in loss of interaction with the SWI/SNF complex, decreases the binding of paraspeckle proteins to chromatin modifiers, transcription factors, and histones. Functionally, the loss of ARID1B and NEAT1 influences the transcription and the alternative splicing of a common set of genes. Our findings reveal that dynamic granules such as the paraspeckles may leverage the specificity of epigenetic modifiers to impart their regulatory effect, thus providing a molecular basis for their function.
    Keywords:  chromatin; lncRNA; paralogs; phase separation; transcription
    DOI:  https://doi.org/10.15252/embr.202255345
  8. Cells. 2022 Oct 26. pii: 3383. [Epub ahead of print]11(21):
    Drug Resistance in Cancers: A Free Pass for Bullying.
    Jing Li, Xiao Li, Qie Guo.
      The cancer burden continues to grow globally, and drug resistance remains a substantial challenge in cancer therapy. It is well established that cancerous cells with clonal dysplasia generate the same carcinogenic lesions. Tumor cells pass on genetic templates to subsequent generations in evolutionary terms and exhibit drug resistance simply by accumulating genetic alterations. However, recent evidence has implied that tumor cells accumulate genetic alterations by progressively adapting. As a result, intratumor heterogeneity (ITH) is generated due to genetically distinct subclonal populations of cells coexisting. The genetic adaptive mechanisms of action of ITH include activating "cellular plasticity", through which tumor cells create a tumor-supportive microenvironment in which they can proliferate and cause increased damage. These highly plastic cells are located in the tumor microenvironment (TME) and undergo extreme changes to resist therapeutic drugs. Accordingly, the underlying mechanisms involved in drug resistance have been re-evaluated. Herein, we will reveal new themes emerging from initial studies of drug resistance and outline the findings regarding drug resistance from the perspective of the TME; the themes include exosomes, metabolic reprogramming, protein glycosylation and autophagy, and the relates studies aim to provide new targets and strategies for reversing drug resistance in cancers.
    Keywords:  autophagy; drug resistance; exosomes; glycosylation; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells11213383
  9. Mol Cancer Ther. 2022 Nov 07. pii: MCT-22-0101. [Epub ahead of print]
    Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death.
    Laura J Jenkins, Ian Y Luk, Walter D Fairlie, Erinna F Lee, Michelle Palmieri, Kael L Schoffer, Tao Tan, Irvin Ng, Natalia Vukelic, Sharon Tran, Janson Wt Tse, Rebecca Nightingale, Zakia Alam, Fiona Chionh, George Iatropoulos, Matthias Ernst, Shoukat Afshar-Sterle, Jayesh Desai, Peter Gibbs, Oliver M Sieber, Amardeep S Dhillon, Niall C Tebbutt, John M Mariadason.
      The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC cell lines respectively. These findings identify a series of ERK/MAPK genotype tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.  .
    DOI:  https://doi.org/10.1158/1535-7163.MCT-22-0101
  10. Results Probl Cell Differ. 2022 ;70 279-294
    Chromatin Dynamics During Entry to Quiescence and Compromised Functionality in Cancer Cells.
    Olivia Grace Dobbs, Dawn Coverley.
      Quiescence is a vital cellular state where cells can reversibly exit the cell cycle and cease proliferation in unfavourable conditions. Cells can undergo multiple transitions in and out of quiescence during their lifetime, and an imbalance in this highly regulated process can promote tumorigenesis and disease. The nucleus experiences vast changes during entry to quiescence, including changes in gene expression and a reduction in size due to increased chromatin compaction. Studies into these changes have highlighted the importance of a core quiescence gene expression programme, reorganisation of nuclear structures, and the action of the condensin complex in creating a stable, quiescent nucleus. However, the underpinning mechanisms behind the formation of a quiescent nucleus are still not fully understood. This chapter explores the current literature surrounding chromatin dynamics during entry to quiescence and the association between quiescence and disease and accentuates the need for further studies to understand this transition. Linking failure to maintain a stable, quiescent state with potential genome instability may help in the advancement of medical interventions for a range of diseases, including cancer.
    Keywords:  Chromatin; Condensin complex; H4K20me; Nuclear condensation; Quiescence
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_9
  11. Results Probl Cell Differ. 2022 ;70 469-494
    Nuclear Organization in Response to Stress: A Special Focus on Nucleoli.
    Enkhzaya Batnasan, Sonja Koivukoski, Minttu Kärkkäinen, Leena Latonen.
      In this chapter, we discuss the nuclear organization and how it responds to different types of stress. A key component in these responses is molecular traffic between the different sub-nucleolar compartments, such as nucleoplasm, chromatin, nucleoli, and various speckle and body compartments. This allows specific repair and response activities in locations where they normally are not active and serve to halt sensitive functions until the stress insult passes and inflicted damage has been repaired. We focus on mammalian cells and their nuclear organization, especially describing the central role of the nucleolus in nuclear stress responses. We describe events after multiple stress types, including DNA damage, various drugs, and toxic compounds, and discuss the involvement of macromolecular traffic between dynamic, phase-separated nuclear organelles and foci. We delineate the key proteins and non-coding RNA in the formation of stress-responsive, non-membranous nuclear organelles, many of which are relevant to the formation of and utilization in cancer treatment.
    Keywords:  Cellular stress; DNA damage; Nucleolus; Nucleus; Proteotoxic stress
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_17
  12. Curr Issues Mol Biol. 2022 Oct 31. 44(11): 5352-5362
    Review on Advanced Cancer Modeling for a Cancer Study.
    Yong-Hee Cho.
      Intensive efforts to develop anti-cancer agents have been made for over 60 years. However, cancer is still considered a lethal disease. To study the best anti-cancer agents for improving the survival rates of cancer patients, many researchers have focused on establishing advanced experimental applications reflecting on the biomimetics of cancer patients involving the heterogeneity of cancer cells. The heterogeneity of cancer cells, which are derived from various clones and affected by different environments, presents different genetic backgrounds and molecular characteristics attributed to the differential responses to cancer therapies, and these are responsible for the resistance to cancer therapies, as well as for recurrence following cancer treatments. Therefore, the development of advanced applications for the cancer patient is expected to help the development of more effective anti-cancer agents. The present review evaluates recently developed cancer models encompassing the heterogeneity of cancer cells, which present similar morphological architecture, genetic backgrounds, and molecular characteristics to corresponding patient tumor tissues.
    Keywords:  cancer organoid; drug screening; organoid; patient-derived tumor organoid; patient-derived tumor xenograft
    DOI:  https://doi.org/10.3390/cimb44110362
  13. Biomedicines. 2022 Nov 07. pii: 2833. [Epub ahead of print]10(11):
    Cellular Prion Protein Role in Cancer Biology: Is It A Potential Therapeutic Target?
    Saba Yousaf, Muhammad Ahmad, Siwen Wu, Muhammad Anjum Zia, Ishtiaq Ahmed, Hafiz M N Iqbal, Qingyou Liu, Saif Ur Rehman.
      Cancers are worldwide health concerns, whether they are sporadic or hereditary. The fundamental mechanism that causes somatic or oncogenic mutations and ultimately aids cancer development is still unknown. However, mammalian cells with protein-only somatic inheritance may also contribute to cancerous malignancies. Emerging data from a recent study show that prion-like proteins and prions (PrPC) are crucial entities that have a functional role in developing neurological disorders and cancer. Furthermore, excessive PrPC expression profiling has also been detected in non-neuronal tissues, such as the lymphoid cells, kidney, GIT, lung, muscle, and mammary glands. PrPC expression is strongly linked with the proliferation and metastasis of pancreatic, prostate, colorectal, and breast malignancies. Similarly, experimental investigation presented that the PrPC expression, including the prion protein-coding gene (PRNP) and p53 ag are directly associated with tumorigenicity and metastasis (tumor suppressor gene). The ERK2 (extracellular signal-regulated kinase) pathway also confers a robust metastatic capability for PrPC-induced epithelial to mesenchymal transition. Additionally, prions could alter the epigenetic regulation of genes and overactive the mitogen-activated protein kinase (MAPK) signaling pathway, which promotes the development of cancer in humans. Protein overexpression or suppression caused by a prion and prion-like proteins has also been linked to oncogenesis and metastasis. Meanwhile, additional studies have discovered resistance to therapeutic targets, highlighting the significance of protein expression levels as potential diagnostic indicators and therapeutic targets.
    Keywords:  EP/MAPK pathway; ERK2 (MAPK1) pathway; PRNP; cancer biology; cancer cell drug resistance; prion; prion protein; therapeutic target
    DOI:  https://doi.org/10.3390/biomedicines10112833
  14. Results Probl Cell Differ. 2022 ;70 625-663
    Nuclear Actin Dynamics in Gene Expression, DNA Repair, and Cancer.
    Yuanjian Huang, Shengzhe Zhang, Jae-Il Park.
      Actin is a highly conserved protein in mammals. The actin dynamics is regulated by actin-binding proteins and actin-related proteins. Nuclear actin and these regulatory proteins participate in multiple nuclear processes, including chromosome architecture organization, chromatin remodeling, transcription machinery regulation, and DNA repair. It is well known that the dysfunctions of these processes contribute to the development of cancer. Moreover, emerging evidence has shown that the deregulated actin dynamics is also related to cancer. This chapter discusses how the deregulation of nuclear actin dynamics contributes to tumorigenesis via such various nuclear events.
    Keywords:  BAF complex; Cancer; Chromatin remodeling; Chromosome architecture; DNA repair; Gene expression; INO80 complex; Nuclear actin; RNA polymerase; Transcription machinery
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_23
  15. Results Probl Cell Differ. 2022 ;70 339-373
    Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Function, and Phenotype.
    Andrew J Fritz, Mohammed El Dika, Rabail H Toor, Princess D Rodriguez, Stephen J Foley, Rahim Ullah, Daijing Nie, Bodhisattwa Banerjee, Dorcas Lohese, Kirsten M Tracy, Karen C Glass, Seth Frietze, Prachi N Ghule, Jessica L Heath, Anthony N Imbalzano, Andre van Wijnen, Jonathan Gordon, Jane B Lian, Janet L Stein, Gary S Stein.
      Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.
    Keywords:  Cell cycle control; Chromatin; Epigenetic control; Histones; Mitotic gene bookmarking; Noncoding RNAs; Nuclear structure; Nucleosomes; Spatial transcriptomics; Transcription; Tumor suppression
    DOI:  https://doi.org/10.1007/978-3-031-06573-6_12
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