bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒06‒11
six papers selected by
Ankita Daiya
BITS Pilani
  1. An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.
  2. Epigenetic markers and therapeutic targets for metastasis.
  3. Heritable transcriptional defects from aberrations of nuclear architecture.
  4. How epigenetics impacts on human diseases.
  5. Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy.
  6. Construction and validation of an oxidative-stress-related risk model for predicting the prognosis of osteosarcoma.
  1. Nat Cancer. 2023 Jun 05.
    An allosteric pan-TEAD inhibitor blocks oncogenic YAP/TAZ signaling and overcomes KRAS G12C inhibitor resistance.
    Thijs J Hagenbeek, Jason R Zbieg, Marc Hafner, Rana Mroue, Jennifer A Lacap, Nicole M Sodir, Cameron L Noland, Shervin Afghani, Ayush Kishore, Kamakoti P Bhat, Xiaosai Yao, Stephen Schmidt, Saundra Clausen, Micah Steffek, Wendy Lee, Paul Beroza, Scott Martin, Eva Lin, Rina Fong, Paola Di Lello, Marta H Kubala, Michelle N-Y Yang, Jeffrey T Lau, Emily Chan, Alfonso Arrazate, Le An, Elizabeth Levy, Maria N Lorenzo, Ho-June Lee, Trang H Pham, Zora Modrusan, Richard Zang, Yi-Chen Chen, Michal Kabza, Musaddeque Ahmed, Jason Li, Matthew T Chang, Danilo Maddalo, Marie Evangelista, Xin Ye, James J Crawford, Anwesha Dey.
      The Hippo pathway is a key growth control pathway that is conserved across species. The downstream effectors of the Hippo pathway, YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif), are frequently activated in cancers to drive proliferation and survival. Based on the premise that sustained interactions between YAP/TAZ and TEADs (transcriptional enhanced associate domain) are central to their transcriptional activities, we discovered a potent small-molecule inhibitor (SMI), GNE-7883, that allosterically blocks the interactions between YAP/TAZ and all human TEAD paralogs through binding to the TEAD lipid pocket. GNE-7883 effectively reduces chromatin accessibility specifically at TEAD motifs, suppresses cell proliferation in a variety of cell line models and achieves strong antitumor efficacy in vivo. Furthermore, we uncovered that GNE-7883 effectively overcomes both intrinsic and acquired resistance to KRAS (Kirsten rat sarcoma viral oncogene homolog) G12C inhibitors in diverse preclinical models through the inhibition of YAP/TAZ activation. Taken together, this work demonstrates the activities of TEAD SMIs in YAP/TAZ-dependent cancers and highlights their potential broad applications in precision oncology and therapy resistance.
    DOI:  https://doi.org/10.1038/s43018-023-00577-0
  2. Cancer Metastasis Rev. 2023 Jun 07.
    Epigenetic markers and therapeutic targets for metastasis.
    Carolyn J Kravitz, Qin Yan, Don X Nguyen.
      The last few years have seen an increasing number of discoveries which collectively demonstrate that histone and DNA modifying enzyme modulate different stages of metastasis. Moreover, epigenomic alterations can now be measured at multiple scales of analysis and are detectable in human tumors or liquid biopsies. Malignant cell clones with a proclivity for relapse in certain organs may arise in the primary tumor as a consequence of epigenomic alterations which cause a loss in lineage integrity. These alterations may occur due to genetic aberrations acquired during tumor progression or concomitant to therapeutic response. Moreover, evolution of the stroma can also alter the epigenome of cancer cells. In this review, we highlight current knowledge with a particular emphasis on leveraging chromatin and DNA modifying mechanisms as biomarkers of disseminated disease and as therapeutic targets to treat metastatic cancers.
    Keywords:  Circulating tumor cells; Epi-drugs; Epigenetic biomarkers; Metastasis; Plasticity
    DOI:  https://doi.org/10.1007/s10555-023-10109-y
  3. Nature. 2023 Jun 07.
    Heritable transcriptional defects from aberrations of nuclear architecture.
    Stamatis Papathanasiou, Nikos A Mynhier, Shiwei Liu, Gregory Brunette, Ema Stokasimov, Etai Jacob, Lanting Li, Caroline Comenho, Bas van Steensel, Jason D Buenrostro, Cheng-Zhong Zhang, David Pellman.
      Transcriptional heterogeneity due to plasticity of the epigenetic state of chromatin contributes to tumour evolution, metastasis and drug resistance1-3. However, the mechanisms that cause this epigenetic variation are incompletely understood. Here we identify micronuclei and chromosome bridges, aberrations in the nucleus common in cancer4,5, as sources of heritable transcriptional suppression. Using a combination of approaches, including long-term live-cell imaging and same-cell single-cell RNA sequencing (Look-Seq2), we identified reductions in gene expression in chromosomes from micronuclei. With heterogeneous penetrance, these changes in gene expression can be heritable even after the chromosome from the micronucleus has been re-incorporated into a normal daughter cell nucleus. Concomitantly, micronuclear chromosomes acquire aberrant epigenetic chromatin marks. These defects may persist as variably reduced chromatin accessibility and reduced gene expression after clonal expansion from single cells. Persistent transcriptional repression is strongly associated with, and may be explained by, markedly long-lived DNA damage. Epigenetic alterations in transcription may therefore be inherently coupled to chromosomal instability and aberrations in nuclear architecture.
    DOI:  https://doi.org/10.1038/s41586-023-06157-7
  4. Eur J Intern Med. 2023 Jun 03. pii: S0953-6205(23)00193-0. [Epub ahead of print]
    How epigenetics impacts on human diseases.
    Antonella Farsetti, Barbara Illi, Carlo Gaetano.
      Epigenetics is a rapidly growing field of biology that studies the changes in gene expression that are not due to alterations in the DNA sequence but rather the chemical modifications of DNA and its associated proteins. Epigenetic mechanisms can profoundly influence gene expression, cell differentiation, tissue development, and disease susceptibility. Understanding epigenetic changes is essential to elucidate the mechanisms underlying the increasingly recognized role of environmental and lifestyle factors in health and disease and the intergenerational transmission of phenotypes. Recent studies suggest epigenetics may be critical in various diseases, from cardiovascular disease and cancer to neurodevelopmental and neurodegenerative disorders. Epigenetic modifications are potentially reversible and could provide new therapeutic avenues for treating these diseases using epigenetic modulators. Moreover, epigenetics provide insight into disease pathogenesis and biomarkers for disease diagnosis and risk stratification. Nevertheless, epigenetic interventions have the potential for unintended consequences and may potentially lead to increased risks of unexpected outcomes, such as adverse drug reactions, developmental abnormalities, and cancer. Therefore, rigorous studies are essential to minimize the risks associated with epigenetic therapies and to develop safe and effective interventions for improving human health. This article provides a synthetic and historical view of the origin of epigenetics and some of the most relevant achievements.
    Keywords:  Chromatin; Chronic disease; DNA; Epigenetic enzyme; Epigenetics; HAT; HDAC; Histone; RNA
    DOI:  https://doi.org/10.1016/j.ejim.2023.05.036
  5. J Nippon Med Sch. 2023 Jun 02.
    Molecular mechanisms of macroautophagy, microautophagy, and chaperone-mediated autophagy.
    Hayashi Yamamoto, Takahide Matsui.
      Autophagy is a self-digestive process that is conserved in eukaryotic cells and responsible for maintaining cellular homeostasis through proteolysis. By this process, cells break down their own components in lysosomes. Autophagy can be classified into three categories: macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Macroautophagy involves membrane elongation and microautophagy involves membrane internalization, and both pathways undergo selective or non-selective processes that transport cytoplasmic components into lysosomes to be degraded. CMA, however, involves selective incorporation of cytosolic materials into lysosomes without membrane deformation. All three categories of autophagy have attracted much attention due to their involvement in various biological phenomena and their relevance to human diseases, such as neurodegenerative diseases and cancer. Clarification of the molecular mechanisms behind these processes is key to understanding autophagy and recent studies have made major progress in this regard, especially for the mechanisms of initiation and membrane elongation in macroautophagy and substrate recognition in microautophagy and CMA. Furthermore, it is becoming evident that the three categories of autophagy are related to each other despite their implementation by different sets of proteins and the involvement of completely different membrane dynamics. In this review, recent progress in macroautophagy, microautophagy, and CMA are summarized.
    Keywords:  CMA; autophagy; macroautophagy; microautophagy
    DOI:  https://doi.org/10.1272/jnms.JNMS.2024_91-102
  6. Aging (Albany NY). 2023 Jun 02. 15
    Construction and validation of an oxidative-stress-related risk model for predicting the prognosis of osteosarcoma.
    Hanning Wang, Juntan Li, Xu Li.
      BACKGROUND: Osteosarcoma is the most common bone malignancy in teenagers, and warrants effective measures for diagnosis and prognosis. Oxidative stress (OS) is the key driver of several cancers and other diseases.METHODS: The TARGET-osteosarcoma database was employed as the training cohort and GSE21257 and GSE39055 was applied for external validation. The patients were classified into the high- and low-risk groups based on the median risk score of each sample. ESTIMATE and CIBERSORT were applied for the evaluation of tumor microenvironment immune infiltration. GSE162454 of single-cell sequencing was employed for analyzing OS-related genes.
    RESULTS: Based on the gene expression and clinical data of 86 osteosarcoma patients in the TARGET database, we identified eight OS-related genes, including MAP3K5, G6PD, HMOX1, ATF4, ACADVL, MAPK1, MAPK10, and INS. In both the training and validation sets, the overall survival of patients in the high-risk group was significantly worse than that in the low-risk group. The ESTIMATE algorithm revealed that patients in the high-risk group had higher tumor purity but lower immune score and stromal score. In addition, the CIBERSORT algorithm showed that the M0 and M2 macrophages were the predominant infiltrating cells in osteosarcoma. Based on the expression analysis of immune checkpoint, CD274(PDL1), CXCL12, BTN3A1, LAG3, and IL10 were identified as potential immune therapy targets. Analysis of the single cell sequencing data also revealed the expression patterns of OS-related genes in different cell types.
    CONCLUSIONS: An OS-related prognostic model can accurately provide the prognosis of osteosarcoma patients, and may help identify suitable candidates for immunotherapy.
    Keywords:  immune microenvironment; nomogram; osteosarcoma; prognosis; single cell sequencing
    DOI:  https://doi.org/10.18632/aging.204764
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