bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2022–01–30
ten papers selected by
Ankita Daiya, Birla Institute of Technology and Science
  1. Profiling the regulatory interplay of BET bromodomains and Sirtuins in cancer cell lines.
  2. The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties.
  3. HBI-8000, HUYABIO Lead Clinical Program, Is a Selective Histone Deacetylase Inhibitor With Therapeutic Benefits in Leukemia and in Solid Tumors.
  4. Degradation of nuclear components via different autophagy pathways.
  5. The role of YAP1 in small cell lung cancer.
  6. Dynamic Activity of Histone H3-Specific Chaperone Complexes in Oncogenesis.
  7. Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors.
  8. Oncogene or Tumor Suppressor: The Coordinative Role of Lysine Methyltransferase SET7/9 in Cancer Development and the Related Mechanisms.
  9. Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces.
  10. Epigenetic landscape of drug responses revealed through large-scale ChIP-seq data analyses.
  1. Biomed Pharmacother. 2022 Jan 19. pii: S0753-3322(22)00040-3. [Epub ahead of print]147 112652
    Profiling the regulatory interplay of BET bromodomains and Sirtuins in cancer cell lines.
    Joni Järvenpää, Minna Rahnasto-Rilla, Maija Lahtela-Kakkonen, Jenni Küblbeck.
      Alterations in epigenetic marking, due to changes in expression or activity of epigenetic regulators, may affect cancer development and progression and thus, targeting epigenetic regulators provides potential avenues for cancer treatment. Bromodomain and extra terminal domain (BET) proteins, epigenetic readers recognizing histone acetylation, and Sirtuins (SIRT1-7), histone deacetylases or erasers, affect the chromatin acetylation status, and thus have a vital role in transcriptional regulation of a variety of cancer-related genes. Here, the effects of three BET inhibitors on SIRT expression were screened in a broad set of cancer cell lines to study the potential interplay of these distinct epigenetic factors in gene regulation. We show that BET inhibitors have distinct effects on SIRTs and their target gene expression in cancer cell lines derived from several solid tumour cancers. This functional link may open further avenues for epigenetic combination therapies for different cancers.
    Keywords:  BET inhibitors; Bromodomain; Cancer; Cancer epigenetics; Sirtuin
    DOI:  https://doi.org/10.1016/j.biopha.2022.112652
  2. Front Oncol. 2021 ;11 814085
    The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties.
    Dingju Wei, Meng Xu, Zhihua Wang, Jingjing Tong.
      Metabolic reprogramming is one of the hallmarks of malignant tumors, which provides energy and material basis for tumor rapid proliferation, immune escape, as well as extensive invasion and metastasis. Blocking the energy and material supply of tumor cells is one of the strategies to treat tumor, however tumor cell metabolic heterogeneity prevents metabolic-based anti-cancer treatment. Therefore, searching for the key metabolic factors that regulate cell cancerous change and tumor recurrence has become a major challenge. Emerging technology--single-cell metabolomics is different from the traditional metabolomics that obtains average information of a group of cells. Single-cell metabolomics identifies the metabolites of single cells in different states by mass spectrometry, and captures the molecular biological information of the energy and substances synthesized in single cells, which provides more detailed information for tumor treatment metabolic target screening. This review will combine the current research status of tumor cell metabolism with the advantages of single-cell metabolomics technology, and explore the role of single-cell sequencing technology in searching key factors regulating tumor metabolism. The addition of single-cell technology will accelerate the development of metabolism-based anti-cancer strategies, which may greatly improve the prognostic survival rate of cancer patients.
    Keywords:  cancer metabolism; metabolic heterogeneity; metabolic reprogramming; single-cell metabolomics; tumor drug resistance
    DOI:  https://doi.org/10.3389/fonc.2021.814085
  3. Front Oncol. 2021 ;11 768685
    HBI-8000, HUYABIO Lead Clinical Program, Is a Selective Histone Deacetylase Inhibitor With Therapeutic Benefits in Leukemia and in Solid Tumors.
    Farbod Shojaei, Bob Goodenow, Gloria Lee, Fairooz Kabbinavar, Mireille Gillings.
      HBI-8000 is a small molecule inhibitor of class I HDACs and has been approved for the treatment of PTCL, ATL and, in combination with exemestane, in a subpopulation of breast cancer. Given the roles of HDACs in normal and cancerous cells, there are currently multiple clinical trials, by HUYABIO International, to test the efficacy of HBI-8000 in monotherapy or in combination settings in leukemias and in solid tumors. The current review is focused on the applications of HDACi HBI-8000 in cancer therapy and its potential in combination with DDR agents.
    Keywords:  HBI-8000; HDACs; MOA; clinical; oncology; tumor immunology
    DOI:  https://doi.org/10.3389/fonc.2021.768685
  4. Trends Cell Biol. 2022 Jan 20. pii: S0962-8924(21)00267-1. [Epub ahead of print]
    Degradation of nuclear components via different autophagy pathways.
    Ziyang Li, Hitoshi Nakatogawa.
      Eukaryotic cells have evolved different modes of autophagy, including macroautophagy and microautophagy, to deliver their own components to lysosomes or vacuoles for degradation. While an increasing body of research has established that autophagy plays pivotal roles for the maintenance and regulation of various cellular constituents, recent studies have begun to reveal that parts of the nucleus, for example, nucleus-derived vesicles and nuclear proteins, also become targets of autophagic degradation in different physiological or pathological contexts, including nutrient deprivation, defective nuclear pore complex (NPC) assembly, DNA damage, cellular senescence, and oncogenic insults. Here, we overview our current knowledge on the mechanisms and physiological roles of these 'nucleophagy' pathways and discuss their possible interplays and remaining issues.
    Keywords:  autophagy; intracellular degradation; lysosomes; nuclear pore complexes; nucleus; vacuoles
    DOI:  https://doi.org/10.1016/j.tcb.2021.12.008
  5. Hum Cell. 2022 Jan 24.
    The role of YAP1 in small cell lung cancer.
    Haruki Saito, Yuki Tenjin, Tatsuya Yamada, Shinji Kudoh, Noritaka Kudo, Mune Sanada, Younosuke Sato, Akira Matsuo, Yorihisa Orita, Takaaki Ito.
      Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ, also known as WWTR1) are core downstream effectors of the Hippo pathway, which is involved in diverse biological processes. The oncogenic effects of YAP and TAZ in non-small cell lung cancer (NSCLC) have recently been reported; however, their roles in SCLC remain unclear. Immunohistochemistry (IHC) on lung cancer tissues and Western blotting (WB) on lung cancer cell lines were performed to examine the expression of YAP1. Genome editing using CRISPR/Cas9 was then used to knockout the YAP1 gene in the H69AR cell line. An RNA-sequence analysis, gene ontology (GO) analysis, WB, cell counting assay, invasion assays, and xenograft studies were conducted on these cells to investigate the biological roles of YAP1. IHC revealed that insulinoma-associated protein 1 was expressed in most cases (28 out of 32 cases), while only four cases expressed YAP1. The knockout of YAP1 in H69AR cells, a chemically induced SCLC-Y subtype, reduced cell proliferation and invasion capacity and restored drug sensitivity. Xenograft assays revealed that the knockout of YAP1 suppressed cell proliferation. Tumor tissues showed the expression of neuroendocrine markers and a low Ki-67 index. In SCLC, YAP1 plays an important role in biological functions, such as cell proliferation, EMT, drug sensitivity, and neuroendocrine differentiation.
    Keywords:  Drug sensitivity; Epithelial–mesenchymal transition (EMT); Neuroendocrine (NE) differentiation; Small cell lung carcinoma (SCLC); YAP1
    DOI:  https://doi.org/10.1007/s13577-022-00669-6
  6. Front Oncol. 2021 ;11 806974
    Dynamic Activity of Histone H3-Specific Chaperone Complexes in Oncogenesis.
    Ting Wen, Qiao Yi Chen.
      Canonical histone H3.1 and variant H3.3 deposit at different sites of the chromatin via distinct histone chaperones. Histone H3.1 relies on chaperone CAF-1 to mediate replication-dependent nucleosome assembly during S-phase, while H3.3 variant is regulated and incorporated into the chromatin in a replication-independent manner through HIRA and DAXX/ATRX. Current literature suggests that dysregulated expression of histone chaperones may be implicated in tumor progression. Notably, ectopic expression of CAF-1 can promote a switch between canonical H3.1 and H3 variants in the chromatin, impair the chromatic state, lead to chromosome instability, and impact gene transcription, potentially contributing to carcinogenesis. This review focuses on the chaperone proteins of H3.1 and H3.3, including structure, regulation, as well as their oncogenic and tumor suppressive functions in tumorigenesis.
    Keywords:  H3.1; H3.3; cancer; chaperone; histone; histone variants
    DOI:  https://doi.org/10.3389/fonc.2021.806974
  7. ChemMedChem. 2022 Jan 24.
    Balancing Histone Deacetylase (HDAC) Inhibition and Drug-likeness: Biological and Physicochemical Evaluation of Class I Selective HDAC Inhibitors.
    Linda Schäker-Hübner, Reza Haschemi, Thomas Büch, Fabian B Kraft, Birke Brumme, Andrea Schöler, Robert Jenke, Jens Meiler, Achim Aigner, Gerd Bendas, Finn Kristian Hansen.
      Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho -aminoanilides targeting the "foot-pocket" in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi fragments related to CI-994  and evaluated their solubility, lipophilicity (log D 7.4 ) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising fragment and transferred its ZBG to our previously published HDACi scaffold featuring a peptoid-based cap group. The resulting hit compound LSH-A54 showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. Subsequent evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties of LSH-A33 and LSH-A54 were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines.
    Keywords:  cancer; drug design; epigenetics; histone deacetylases; inhibitors
    DOI:  https://doi.org/10.1002/cmdc.202100755
  8. J Cancer. 2022 ;13(2): 623-640
    Oncogene or Tumor Suppressor: The Coordinative Role of Lysine Methyltransferase SET7/9 in Cancer Development and the Related Mechanisms.
    Ye Gu, Xiaofeng Zhang, Weiping Yu, Weifeng Dong.
      SET7/9 is a member of the protein lysine methyltransferase family that methylates both histone 3 lysine 4 (H3-K4) and lysine(s) of other non-histone proteins. In recent years, dis-regulation of SET7/9 were frequently detected in various cancer types and SET7/9-mediated methylation has been recognized as an important mechanism that affects cancer initiation and development through regulation of a series of cellular processes. Here we review the currently identified histone and non-histone protein targets of SET7/9 that are closely correlated with human cancer and the function of SET7/9 in regulating the expression and stability of its protein targets. The review also discusses the putative role of SET7/9 as an oncogene or tumor suppressor in the development of various cancer types and the underlying mechanisms, which may help better evaluate the potential of SET7/9 as a novel candidate for cancer therapy.
    Keywords:  SET7/9; cancer developments; lysine methyltransferase; methylation
    DOI:  https://doi.org/10.7150/jca.57663
  9. Soft Matter. 2022 Jan 28.
    Towards an integrative understanding of cancer mechanobiology: calcium, YAP, and microRNA under biophysical forces.
    Chenyu Liang, Miao Huang, Tianqi Li, Lu Li, Hayley Sussman, Yao Dai, Dietmar W Siemann, Mingyi Xie, Xin Tang.
      An increasing number of studies have demonstrated the significant roles of the interplay between microenvironmental mechanics in tissues and biochemical-genetic activities in resident tumor cells at different stages of tumor progression. Mediated by molecular mechano-sensors or -transducers, biomechanical cues in tissue microenvironments are transmitted into the tumor cells and regulate biochemical responses and gene expression through mechanotransduction processes. However, the molecular interplay between the mechanotransduction processes and intracellular biochemical signaling pathways remains elusive. This paper reviews the recent advances in understanding the crosstalk between biomechanical cues and three critical biochemical effectors during tumor progression: calcium ions (Ca2+), yes-associated protein (YAP), and microRNAs (miRNAs). We address the molecular mechanisms underpinning the interplay between the mechanotransduction pathways and each of the three effectors. Furthermore, we discuss the functional interactions among the three effectors in the context of soft matter and mechanobiology. We conclude by proposing future directions on studying the tumor mechanobiology that can employ Ca2+, YAP, and miRNAs as novel strategies for cancer mechanotheraputics. This framework has the potential to bring insights into the development of novel next-generation cancer therapies to suppress and treat tumors.
    DOI:  https://doi.org/10.1039/d1sm01618k
  10. BMC Bioinformatics. 2022 Jan 24. 23(1): 51
    Epigenetic landscape of drug responses revealed through large-scale ChIP-seq data analyses.
    Zhaonan Zou, Michio Iwata, Yoshihiro Yamanishi, Shinya Oki.
       BACKGROUND: Elucidating the modes of action (MoAs) of drugs and drug candidate compounds is critical for guiding translation from drug discovery to clinical application. Despite the development of several data-driven approaches for predicting chemical-disease associations, the molecular cues that organize the epigenetic landscape of drug responses remain poorly understood.
    RESULTS: With the use of a computational method, we attempted to elucidate the epigenetic landscape of drug responses, in terms of transcription factors (TFs), through large-scale ChIP-seq data analyses. In the algorithm, we systematically identified TFs that regulate the expression of chemically induced genes by integrating transcriptome data from chemical induction experiments and almost all publicly available ChIP-seq data (consisting of 13,558 experiments). By relating the resultant chemical-TF associations to a repository of associated proteins for a wide range of diseases, we made a comprehensive prediction of chemical-TF-disease associations, which could then be used to account for drug MoAs. Using this approach, we predicted that: (1) cisplatin promotes the anti-tumor activity of TP53 family members but suppresses the cancer-inducing function of MYCs; (2) inhibition of RELA and E2F1 is pivotal for leflunomide to exhibit antiproliferative activity; and (3) CHD8 mediates valproic acid-induced autism.
    CONCLUSIONS: Our proposed approach has the potential to elucidate the MoAs for both approved drugs and candidate compounds from an epigenetic perspective, thereby revealing new therapeutic targets, and to guide the discovery of unexpected therapeutic effects, side effects, and novel targets and actions.
    Keywords:  ChIP-seq; Drug modes of action; Epigenetic landscape; Transcription factor; Transcriptome
    DOI:  https://doi.org/10.1186/s12859-022-04571-8
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