bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023–12–24
twelve papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.
  2. Polycomb Repressive Complex 2 in Oncology.
  3. Unleashing the Power of Yes-Associated Protein in Ferroptosis and Drug Resistance in Breast Cancer, with a Special Focus on Therapeutic Strategies.
  4. Histone Readers and Their Roles in Cancer.
  5. Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.
  6. Inferring the Cancer Cellular Epigenome Heterogeneity via DNA Methylation Patterns.
  7. Regulation of protein synthesis and stability by mechanical cues and its implications in cancer.
  8. From cellular to fear memory: An epigenetic toolbox to remember.
  9. Knocking off cancer's HAT: CSS1477 disrupts oncogenic programs.
  10. Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.
  11. Extracellular matrix detached cancer cells resist oxidative stress by increasing histone demethylase KDM6 activity.
  12. Churros: A docker-based pipeline for large-scale epigenomic analysis.
  1. Elife. 2023 Dec 21. pii: RP88508. [Epub ahead of print]12
    Pharmacological inhibition of CLK2 activates YAP by promoting alternative splicing of AMOTL2.
    Maya L Bulos, Edyta M Grzelak, Chloris Li-Ma, Emily Chen, Mitchell Hull, Kristen A Johnson, Michael J Bollong.
      Yes-associated protein (YAP), the downstream effector of the evolutionarily conserved Hippo pathway, promotes cellular proliferation and coordinates certain regenerative responses in mammals. Small molecule activators of YAP may, therefore, display therapeutic utility in treating disease states involving insufficient proliferative repair. From a high-throughput chemical screen of the comprehensive drug repurposing library ReFRAME, here we report the identification of SM04690, a clinical stage inhibitor of CLK2, as a potent activator of YAP-driven transcriptional activity in cells. CLK2 inhibition promotes alternative splicing of the Hippo pathway protein AMOTL2, producing an exon-skipped gene product that can no longer associate with membrane-bound proteins, resulting in decreased phosphorylation and membrane localization of YAP. This study reveals a novel mechanism by which pharmacological perturbation of alternative splicing inactivates the Hippo pathway and promotes YAP-dependent cellular growth.
    Keywords:  YAP; alternative splicing; biochemistry; cell biology; chemical biology; human; regenerative medicine
    DOI:  https://doi.org/10.7554/eLife.88508
  2. Cancer Treat Res. 2023 ;190 273-320
    Polycomb Repressive Complex 2 in Oncology.
    Yiran Guo, Yao Yu, Gang Greg Wang.
      Dynamic regulation of the chromatin state by Polycomb Repressive Complex 2 (PRC2) provides an important mean for epigenetic gene control that can profoundly influence normal development and cell lineage specification. PRC2 and PRC2-induced methylation of histone H3 lysine 27 (H3K27) are critically involved in a wide range of DNA-templated processes, which at least include transcriptional repression and gene imprinting, organization of three-dimensional chromatin structure, DNA replication and DNA damage response and repair. PRC2-based genome regulation often goes wrong in diseases, notably cancer. This chapter discusses about different modes-of-action through which PRC2 and EZH2, a catalytic subunit of PRC2, mediate (epi)genomic and transcriptomic regulation. We will also discuss about how alteration or mutation of the PRC2 core or axillary component promotes oncogenesis, how post-translational modification regulates functionality of EZH2 and PRC2, and how PRC2 and other epigenetic pathways crosstalk. Lastly, we will briefly touch on advances in targeting EZH2 and PRC2 dependence as cancer therapeutics.
    Keywords:  Cancer; Chromatin; EZH2; H3K27me3; Histone; PRC2; Polycomb; Post-translational modification; Transcription
    DOI:  https://doi.org/10.1007/978-3-031-45654-1_9
  3. Cancers (Basel). 2023 Dec 06. pii: 5728. [Epub ahead of print]15(24):
    Unleashing the Power of Yes-Associated Protein in Ferroptosis and Drug Resistance in Breast Cancer, with a Special Focus on Therapeutic Strategies.
    RamaRao Malla, Durga Bhavani Kundrapu, Priyamvada Bhamidipati, Ganji Purnachandra Nagaraju, Nethaji Muniraj.
      The YAP protein is a critical oncogenic mediator within the Hippo signaling pathway and has been implicated in various cancer types. In breast cancer, it frequently becomes activated, thereby contributing to developing drug-resistance mechanisms. Recent studies have underscored the intricate interplay between YAP and ferroptosis within the breast tumor microenvironment. YAP exerts a negative regulatory effect on ferroptosis, promoting cancer cell survival and drug resistance. This review offers a concise summary of the current understanding surrounding the interplay between the YAP pathway, ferroptosis, and drug-resistance mechanisms in both bulk tumor cells and cancer stem cells. We also explore the potential of natural compounds alone or in combination with anticancer therapies for targeting the YAP pathway in treating drug-resistant breast cancer. This approach holds the promise of enhancing the effectiveness of current treatments and paving the way for developing novel therapeutics.
    Keywords:  Hippo-YAP pathway; breast cancer; drug resistance; ferroptosis; natural compounds
    DOI:  https://doi.org/10.3390/cancers15245728
  4. Cancer Treat Res. 2023 ;190 245-272
    Histone Readers and Their Roles in Cancer.
    Hong Wen, Xiaobing Shi.
      Histone proteins in eukaryotic cells are subjected to a wide variety of post-translational modifications, which are known to play an important role in the partitioning of the genome into distinctive compartments and domains. One of the major functions of histone modifications is to recruit reader proteins, which recognize the epigenetic marks and transduce the molecular signals in chromatin to downstream effects. Histone readers are defined protein domains with well-organized three-dimensional structures. In this Chapter, we will outline major histone readers, delineate their biochemical and structural features in histone recognition, and describe how dysregulation of histone readout leads to human cancer.
    DOI:  https://doi.org/10.1007/978-3-031-45654-1_8
  5. Cell Death Discov. 2023 Dec 22. 9(1): 470
    Super-enhancers and the super-enhancer reader BRD4: tumorigenic factors and therapeutic targets.
    Haihong Qian, Min Zhu, Xinyu Tan, Yixing Zhang, Xiangning Liu, Li Yang.
      Transcriptional super-enhancers and the BET bromodomain protein BRD4 are emerging as critical drivers of tumorigenesis and therapeutic targets. Characterized by substantial accumulation of histone H3 lysine 27 acetylation (H3K27ac) signals at the loci of cell identity genes and critical oncogenes, super-enhancers are recognized, bound and activated by BRD4, resulting in considerable oncogene over-expression, malignant transformation, cancer cell proliferation, survival, tumor initiation and progression. Small molecule compound BRD4 BD1 and BD2 bromodomain inhibitors block BRD4 binding to super-enhancers, suppress oncogene transcription and expression, reduce cancer cell proliferation and survival, and repress tumor progression in a variety of cancer types. Like other targeted therapy agents, BRD4 inhibitors show moderate anticancer effects on their own, and exert synergistic anticancer effects in vitro and in preclinical models, when combined with other anticancer agents including CDK7 inhibitors, CBP/p300 inhibitors and histone deacetylase inhibitors. More recently, BRD4 BD2 bromodomain selective inhibitors, proteolysis-targeting chimera (PROTAC) BRD4 protein degraders, and dual BRD4 and CBP/p300 bromodomain co-inhibitors have been developed and shown better anticancer efficacy and/or safety profile. Importantly, more than a dozen BRD4 inhibitors have entered clinical trials in patients with cancer of various organ origins. In summary, super-enhancers and their reader BRD4 are critical tumorigenic drivers, and BRD4 BD1 and BD2 bromodomain inhibitors, BRD4 BD2 bromodomain selective inhibitors, PROTAC BRD4 protein degraders, and dual BRD4 and CBP/p300 bromodomain co-inhibitors are promising novel anticancer agents for clinical translation.
    DOI:  https://doi.org/10.1038/s41420-023-01775-6
  6. Cancer Treat Res. 2023 ;190 375-393
    Inferring the Cancer Cellular Epigenome Heterogeneity via DNA Methylation Patterns.
    Sheng Li.
      Tumor cells evolve through space and time, generating genetically and phenotypically diverse cancer cell populations that are continually subjected to the selection pressures of their microenvironment and cancer treatment.
    DOI:  https://doi.org/10.1007/978-3-031-45654-1_12
  7. Curr Opin Cell Biol. 2023 Dec 18. pii: S0955-0674(23)00153-9. [Epub ahead of print]86 102304
    Regulation of protein synthesis and stability by mechanical cues and its implications in cancer.
    Sara Göransson, Staffan Strömblad.
      Elevated tissue stiffness is a common feature of many solid tumors and the downstream mechanical signaling affects many cellular processes and contributes to cancer progression. Significant progress has been made in understanding how the mechanical properties of the matrix affect cancer cell behavior as well as transcription. However, how the same mechanical cues impact protein synthesis and stability and how this may contribute to disease is less well understood. Here, we present emerging evidence that cancer progression is frequently supported by gene regulation acting beyond the mRNA level and highlight some of the known crosstalk between this type of regulation and mechanotransduction in cancer as well as in other contexts. We suggest that future systematic approaches to define mechanosensitive translatomes and proteomes and how these are controlled may provide novel targets for cancer therapy.
    DOI:  https://doi.org/10.1016/j.ceb.2023.102304
  8. Curr Opin Neurobiol. 2023 Dec 20. pii: S0959-4388(23)00154-X. [Epub ahead of print]84 102829
    From cellular to fear memory: An epigenetic toolbox to remember.
    Davide Martino Coda, Johannes Gräff.
      Throughout development, the neuronal epigenome is highly sensitive to external stimuli, yet capable of safeguarding cellular memory for a lifetime. In the adult brain, memories of fearful experiences are rapidly instantiated, yet can last for decades, but the mechanisms underlying such longevity remain unknown. Here, we showcase how fear memory formation and storage - traditionally thought to exclusively affect synapse-based events - elicit profound and enduring changes to the chromatin, proposing epigenetic regulation as a plausible molecular template for mnemonic processes. By comparing these to mechanisms occurring in development and differentiation, we notice that an epigenetic machinery similar to that preserving cellular memories might be employed by brain cells so as to form, store, and retrieve behavioral memories.
    Keywords:  Cellular memory; Chromatin; DNA methylation; Epigenetic memory; Fear learning; Posttranslational histone modifications
    DOI:  https://doi.org/10.1016/j.conb.2023.102829
  9. Cell Chem Biol. 2023 Dec 21. pii: S2451-9456(23)00428-2. [Epub ahead of print]30(12): 1505-1507
    Knocking off cancer's HAT: CSS1477 disrupts oncogenic programs.
    Luyao Kevin Xu, Panagiotis Ntziachristos.
      EP300/CBP are histone acetyltransferases recruited onto chromatin by oncogenic transcription factors and control the transcriptional program via their activity in enhancer areas. In the December issue of Cancer Cell, Nicosia et al.1 offer new promise in targeting EP300/CBP using the small-molecule inhibitor CSS1477 in patients with blood tumors and no other therapeutic options.
    DOI:  https://doi.org/10.1016/j.chembiol.2023.11.014
  10. Mol Psychiatry. 2023 Dec 20.
    Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.
    Valentin Ioannidis, Rakshita Pandey, Helen Friedericke Bauer, Michael Schön, Jürgen Bockmann, Tobias M Boeckers, Anne-Kathrin Lutz.
      The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.
    DOI:  https://doi.org/10.1038/s41380-023-02362-y
  11. Saudi J Biol Sci. 2024 Jan;31(1): 103871
    Extracellular matrix detached cancer cells resist oxidative stress by increasing histone demethylase KDM6 activity.
    Mohamed A Alfaleh, Mohammed Razeeth Shait Mohammed, Anwar M Hashem, Turki S Abujamel, Nabil A Alhakamy, Mohammad Imran Khan.
      Epithelial cancer cells rely on the extracellular matrix (ECM) attachment in order to spread to other organs. Detachment from the ECM is necessary for these cells to seed in other locations. When the attachment to the ECM is lost, cellular metabolism undergoes a significant shift from oxidative metabolism to glycolysis. Additionally, the cancer cells become more dependent on glutaminolysis to avoid a specific type of cell death known as anoikis, which is associated with ECM detachment. In our recent study, we observed increased expression of H3K27me3 demethylases, specifically KDM6A/B, in cancer cells that were resistant to anoikis. Since KDM6A/B is known to regulate cellular metabolism, we investigated the effects of suppressing KDM6A/B with GSK-J4 on the metabolic processes in these anoikis-resistant cancer cells. Our results from untargeted metabolomics revealed a profound impact of KDM6A/B inhibition on various metabolic pathways, including glycolysis, methyl histidine, spermine, and glutamate metabolism. Inhibition of KDM6A/B led to elevated reactive oxygen species (ROS) levels and depolarization of mitochondria, while reducing the levels of glutathione, an important antioxidant, by diminishing the intermediates of the glutamate pathway. Glutamate is crucial for maintaining a pool of reduced glutathione. Furthermore, we discovered that KDM6A/B regulates the key glycolytic genes expression like hexokinase, lactate dehydrogenase, and GLUT-1, which are essential for sustaining glycolysis in anoikis-resistant cancer cells. Overall, our findings demonstrated the critical role of KDM6A/B in maintaining glycolysis, glutamate metabolism, and glutathione levels. Inhibition of KDM6A/B disrupts these metabolic processes, leading to increased ROS levels and triggering cell death in anoikis-resistant cancer cells.
    Keywords:  Anoikis resistant; Glycolysis; KDM6A/B; Oxidative stress; ROS
    DOI:  https://doi.org/10.1016/j.sjbs.2023.103871
  12. DNA Res. 2023 Dec 15. pii: dsad026. [Epub ahead of print]
    Churros: A docker-based pipeline for large-scale epigenomic analysis.
    Jiankang Wang, Ryuichiro Nakato.
      The epigenome, which reflects the modifications on chromatin or DNA sequences, provides crucial insight into gene expression regulation and cellular activity. With the continuous accumulation of epigenomic datasets such as chromatin immunoprecipitation followed by sequencing (ChIP-seq) data, there is a great demand for a streamlined pipeline to consistently process them, especially for large-dataset comparisons involving hundreds of samples. Here we present Churros, an end-to-end epigenomic analysis pipeline that is environmentally independent and optimized for handling large-scale data. We successfully demonstrated the effectiveness of Churros by analyzing large-scale ChIP-seq datasets with the hg38 or Telomere-to-Telomere (T2T) human reference genome. We found that applying T2T to the typical analysis workflow has important impacts on read mapping, quality checks, and peak calling. We also introduced a useful feature to study context-specific epigenomic landscapes. Churros will contribute a comprehensive and unified resource for analyzing large-scale epigenomic data.
    Keywords:  Bioinformatics pipeline; Docker; Epigenomics analysis; Large-scale ChIP-seq; T2T genome
    DOI:  https://doi.org/10.1093/dnares/dsad026
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