bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒10‒15
eight papers selected by
Ankita Daiya, Birla Institute of Technology and Science



  1. Cancers (Basel). 2023 Sep 24. pii: 4701. [Epub ahead of print]15(19):
      The Hippo pathway transcriptional co-activators, YES-associated protein (YAP) and Transcriptional Co-Activator with PDZ Binding Motif (TAZ), have both been linked to tumor progression and metastasis. These two proteins possess overlapping and distinct functions, and their activities lead to the expression of genes involved in multiple cellular processes, including cell proliferation, survival, and migration. The dysregulation of YAP/TAZ-dependent cellular processes can result in altered tumor growth and metastasis. In addition to their well-documented roles in the regulation of cancer cell growth, survival, migration, and invasion, the YAP/TAZ-dependent signaling pathways have been more recently implicated in cellular processes that promote metastasis and therapy resistance in several solid tumor types. This review highlights the role of YAP/TAZ signaling networks in the regulation of tumor cell plasticity mediated by hybrid and reversible epithelial-mesenchymal transition (EMT) states, and the promotion of cancer stem cell/progenitor phenotypes. Mechanistically, YAP and TAZ regulate these cellular processes by targeting transcriptional networks. In this review, we detail recently uncovered mechanisms whereby YAP and TAZ mediate tumor growth, metastasis, and therapy resistance, and discuss new therapeutic strategies to target YAP/TAZ function in various solid tumor types. Understanding the distinct and overlapping roles of YAP and TAZ in multiple cellular processes that promote tumor progression to metastasis is expected to enable the identification of effective therapies to treat solid tumors through the hyper-activation of YAP and TAZ.
    Keywords:  TEAD-dependent transcription; YAP/TAZ signaling; therapeutic strategies; transcriptional targets; tumor metastasis
    DOI:  https://doi.org/10.3390/cancers15194701
  2. Cells. 2023 Sep 27. pii: 2370. [Epub ahead of print]12(19):
      Different studies have reported that inhibiting the mevalonate pathway with statins may increase the sensitivity of cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), although the signaling mechanism leading to this sensitization remains largely unknown. We investigated the role of the YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex in the metabolic control of TRAIL sensitivity by the mevalonate pathway. We show that depleting nuclear YAP/TAZ in tumor cells, either via treatment with statins or by silencing YAP/TAZ expression with siRNAs, facilitates the activation of apoptosis by TRAIL. Furthermore, the blockage of TEAD transcriptional activity either pharmacologically or through the ectopic expression of a disruptor of the YAP/TAZ interaction with TEAD transcription factors, overcomes the resistance of tumor cells to the induction of apoptosis by TRAIL. Our results show that the mevalonate pathway controls cellular the FLICE-inhibitory protein (cFLIP) expression in tumor cells. Importantly, inhibiting the YAP/TAZ-TEAD signaling pathway induces cFLIP down-regulation, leading to a marked sensitization of tumor cells to apoptosis induction by TRAIL. Our data suggest that a combined strategy of targeting TEAD activity and selectively activating apoptosis signaling by agonists of apoptotic TRAIL receptors could be explored as a potential therapeutic approach in cancer treatment.
    Keywords:  TNF-related apoptosis-inducing ligand; YAP/TAZ-TEAD; cellular FLICE-like inhibitory protein; mevalonate pathway; statins
    DOI:  https://doi.org/10.3390/cells12192370
  3. Clin Epigenetics. 2023 Oct 11. 15(1): 161
      BACKGROUND: Previous studies have traditionally attributed the initiation of cancer cells to genetic mutations, considering them as the fundamental drivers of carcinogenesis. However, recent research has shed light on the crucial role of epigenomic alterations in various cell types present within the tumor microenvironment, suggesting their potential contribution to tumor formation and progression. Despite these significant findings, the progress in understanding the epigenetic mechanisms regulating tumor heterogeneity has been impeded over the past few years due to the lack of appropriate technical tools and methodologies.RESULTS: The emergence of single-cell sequencing has enhanced our understanding of the epigenetic mechanisms governing tumor heterogeneity by revealing the distinct epigenetic layers of individual cells (chromatin accessibility, DNA/RNA methylation, histone modifications, nucleosome localization) and the diverse omics (transcriptomics, genomics, multi-omics) at the single-cell level. These technologies provide us with new insights into the molecular basis of intratumoral heterogeneity and help uncover key molecular events and driving mechanisms in tumor development.
    CONCLUSION: This paper provides a comprehensive review of the emerging analytical and experimental approaches of single-cell sequencing in various omics, focusing specifically on epigenomics. These approaches have the potential to capture and integrate multiple dimensions of individual cancer cells, thereby revealing tumor heterogeneity and epigenetic features. Additionally, this paper outlines the future trends of these technologies and their current technical limitations.
    Keywords:  Epigenome; Multi-omics; Single-cell sequencing; Tumor heterogeneity
    DOI:  https://doi.org/10.1186/s13148-023-01574-x
  4. J Invest Surg. 2023 Dec;36(1): 2266732
      OBJECTIVE: The inhibition of the Hippo pathway through targeting the Yes-associated protein (YAP) presents a novel and promising approach for treating tumors. However, the efficacy of YAP inhibitors in the context of breast cancer (BC) remains incompletely understood. Here, we aimed to investigate the involvement of YAP in BC's metabolic reprogramming and reveal the potential underlying mechanisms. To this end, we assessed the function of verteporfin (VP), a YAP-TEAD complex inhibitor, on the glycolytic activity of BC cells.METHODS: We evaluated the expression of YAP by utilizing immunohistochemistry (IHC) in BC patients who have undergone 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) prior to biopsy/surgery. We employed RNA immunoprecipitation (RIP) and fluorescent in situ hybridization (FISH) assays to assess the interaction between YAP mRNA and human antigen R (HuR) in BC cells. The biological importance of YAP in the metabolism and malignancy of BC was evaluated in vitro. Finally, the effect of VP on glycolysis was determined by using 18F-FDG uptake, glucose consumption, and lactate production assays.
    RESULTS: Our studies revealed that high expression of YAP was positively correlated with the maximum uptake value (SUVmax) determined by 18F-FDG PET/CT imaging in BC samples. Inhibition of YAP activity suppressed glycolysis in BC. The mechanism underlying this phenomenon could be the binding of YAP to HuR, which promotes glycolysis in BC cells. Treatment with VP effectively suppressed glycolysis induced by YAP overexpression in BC cells.
    CONCLUSION: VP exhibited anti-glycolytic effect on BC cells, indicating its therapeutic value as an FDA-approved drug.
    Keywords:  18F-FDG; Breast cancer; HuR; YAP; glycolysis; verteporfin
    DOI:  https://doi.org/10.1080/08941939.2023.2266732
  5. Mol Biol Rep. 2023 Oct 07.
      Anxiety disorders (ADs) are extremely common psychiatric conditions that frequently co-occur with other physical and mental disorders. The pathophysiology of ADs is multifaceted and involves intricate connections among biological elements, environmental stimuli, and psychological mechanisms. Recent discoveries have highlighted the significance of epigenetics in bridging the gap between multiple risk factors that contribute to ADs and expanding our understanding of the pathomechanisms underlying ADs. Epigenetics is the study of how changes in the environment and behavior can have an impact on gene function. Indeed, researchers have found that epigenetic mechanisms can affect how genes are activated or inactivated, as well as whether they are expressed. Such mechanisms may also affect how ADs form and are protected. That is, the bulk of pharmacological trials evaluating epigenetic treatments for the treatment of ADs have used histone deacetylase inhibitors (HDACi), yielding promising outcomes in both preclinical and clinical studies. This review will provide an outline of how epigenetic pathways can be used to treat ADs or lessen their risk. It will also present the findings from preclinical and clinical trials that are currently available on the use of epigenetic drugs to treat ADs.
    Keywords:  Anxiety Disorders; DNA methylation; Epigenetic; Histone modifications
    DOI:  https://doi.org/10.1007/s11033-023-08787-6
  6. Autophagy. 2023 Oct 10. 1-2
      SQSTM1/p62 bodies are phase-separated condensates that play a fundamental role in intracellular quality control and stress responses. Despite extensive studies investigating the mechanism of formation and degradation of SQSTM1/p62 bodies, the constituents of SQSTM1/p62 bodies remain elusive. We recently developed a purification method for intracellular SQSTM1/p62 bodies using a cell sorter and identified their constituents by mass spectrometry. Combined with mass spectrometry of tissues from selective autophagy-deficient mice, we identified vault, a ubiquitous non-membranous organelle composed of proteins and non-coding RNA, as a novel substrate for selective autophagy. Vault directly binds to NBR1, an SQSTM1/p62 binding partner recruited to SQSTM1/p62 bodies, and is subsequently degraded by selective autophagy dependent on the phase separation of SQSTM1/p62. We named this process "vault-phagy" and found that defects in vault-phagy are related to nonalcoholic steatohepatitis (NASH)-derived hepatocellular carcinoma. Our method for purifying SQSTM1/p62 bodies will contribute to elucidating the mechanisms of several stress responses and diseases mediated by SQSTM1/p62 bodies.
    Keywords:  Fluorescence-activated particle sorting; Mallory-Denk bodies; NBR1; liquid-liquid phase separation; nonalcoholic steatohepatitis; selective autophagy
    DOI:  https://doi.org/10.1080/15548627.2023.2266996
  7. Cell Death Differ. 2023 Oct 12.
      Identification of mutations in histones in a number of human neoplasms and developmental syndromes represents the most compelling evidence to date for a causal role of epigenetic perturbations in human disease. In most cases, these mutations have gain of function properties that cause deviation from normal developmental processes leading to embryo defects and/or neoplastic transformation. These exciting discoveries represent a step-change in our understanding of the role of chromatin (dys)regulation in development and disease. However, the mechanisms of action of oncogenic histone mutations (oncohistones) remain only partially understood. Here, we critically assess existing literature on oncohistones focussing mainly on bone neoplasms. We show how it is possible to draw parallels with some of the cell-autonomous mechanisms of action described in paediatric brain cancer, although the functions of oncohistones in bone tumours remain under-investigated. In this respect, it is becoming clear that histone mutations targeting the same residues display, at least in part, tissue-specific oncogenic mechanisms. Furthermore, it is emerging that cancer cells carrying oncohistones can modify the surrounding microenvironment to support growth and/or alter differentiation trajectories. A better understanding of oncohistone function in different neoplasms provide potential for identification of signalling that could be targeted therapeutically. Finally, we discuss some of the main concepts and future directions in this research area, while also drawing possible connections and parallels with other cancer epigenetic mechanisms.
    DOI:  https://doi.org/10.1038/s41418-023-01227-9
  8. Nucleic Acids Res. 2023 Oct 12. pii: gkad824. [Epub ahead of print]
      Advancements in mass spectrometry (MS)-based proteomics have greatly facilitated the large-scale quantification of proteins and microproteins, thereby revealing altered signalling pathways across many different cancer types. However, specialized and comprehensive resources are lacking for cancer proteomics. Here, we describe CancerProteome (http://bio-bigdata.hrbmu.edu.cn/CancerProteome), which functionally deciphers and visualizes the proteome landscape in cancer. We manually curated and re-analyzed publicly available MS-based quantification and post-translational modification (PTM) proteomes, including 7406 samples from 21 different cancer types, and also examined protein abundances and PTM levels in 31 120 proteins and 4111 microproteins. Six major analytical modules were developed with a view to describe protein contributions to carcinogenesis using proteome analysis, including conventional analyses of quantitative and the PTM proteome, functional enrichment, protein-protein associations by integrating known interactions with co-expression signatures, drug sensitivity and clinical relevance analyses. Moreover, protein abundances, which correlated with corresponding transcript or PTM levels, were evaluated. CancerProteome is convenient as it allows users to access specific proteins/microproteins of interest using quick searches or query options to generate multiple visualization results. In summary, CancerProteome is an important resource, which functionally deciphers the cancer proteome landscape and provides a novel insight for the identification of tumor protein markers in cancer.
    DOI:  https://doi.org/10.1093/nar/gkad824