bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2023‒07‒09
six papers selected by
Ankita Daiya
BITS Pilani

  1. Proc Natl Acad Sci U S A. 2023 07 11. 120(28): e2301285120
      Yes-associated protein (YAP) is a key mechanotransduction protein in diverse physiological and pathological processes; however, a ubiquitous YAP activity regulatory mechanism in living cells has remained elusive. Here, we show that YAP nuclear translocation is highly dynamic during cell movement and is driven by nuclear compression arising from cell contractile work. We resolve the mechanistic role of cytoskeletal contractility in nuclear compression by manipulation of nuclear mechanics. Disrupting the linker of nucleoskeleton and cytoskeleton complex reduces nuclear compression for a given contractility and correspondingly decreases YAP localization. Conversely, decreasing nuclear stiffness via silencing of lamin A/C increases nuclear compression and YAP nuclear localization. Finally, using osmotic pressure, we demonstrated that nuclear compression even without active myosin or filamentous actin regulates YAP localization. The relationship between nuclear compression and YAP localization captures a universal mechanism for YAP regulation with broad implications in health and biology.
    Keywords:  Nucleus; YAP; biophysics; cell mechanics; mechanotransduction
  2. ArXiv. 2023 Jun 13. pii: arXiv:2306.08096v1. [Epub ahead of print]
      Recent evidence suggests that nongenetic (epigenetic) mechanisms play an important role at all stages of cancer evolution. In many cancers, these mechanisms have been observed to induce dynamic switching between two or more cell states, which commonly show differential responses to drug treatments. To understand how these cancers evolve over time, and how they respond to treatment, we need to understand the state-dependent rates of cell proliferation and phenotypic switching. In this work, we propose a rigorous statistical framework for estimating these parameters, using data from commonly performed cell line experiments, where phenotypes are sorted and expanded in culture. The framework explicitly models the stochastic dynamics of cell division, cell death and phenotypic switching, and it provides likelihood-based confidence intervals for the model parameters. The input data can be either the fraction of cells or the number of cells in each state at one or more time points. Through a combination of theoretical analysis and numerical simulations, we show that when cell fraction data is used, the rates of switching may be the only parameters that can be estimated accurately. On the other hand, using cell number data enables accurate estimation of the net division rate for each phenotype, and it can even enable estimation of the state-dependent rates of cell division and cell death. We conclude by applying our framework to a publicly available dataset.
  3. Trends Plant Sci. 2023 Jul 01. pii: S1360-1385(23)00198-X. [Epub ahead of print]
      Histone deacetylases (HDACs) are important chromatin regulators essential for plant tolerance to adverse environments. In addition to histone deacetylation and epigenetic regulation, HDACs deacetylate non-histone proteins and thereby regulate multiple pathways. Like other post-translational modifications (PTMs), acetylation/deacetylation is a reversible switch regulating different cellular processes in plants. Here, by focusing on results obtained in arabidopsis (Arabidopsis thaliana) and rice plants, we analyze the different aspects of HDAC functions and the underlying regulatory mechanisms in modulating plant responses to stress. We hypothesize that, in addition to epigenetic regulation of gene expression, HDACs can also control plant tolerance to stress by regulating transcription, translation, and metabolic activities and possibly assembly-disassembly of stress granules (SGs) through lysine deacetylation of non-histone proteins.
    Keywords:  histone deacetylase; metabolic enzymes; protein lysine acetylation/acylation; stress granules; transcription factors
  4. Nat Commun. 2023 07 03. 14(1): 3907
      YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.
  5. Nature. 2023 Jul 05.
      Acquired drug resistance to anticancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1-4, the underlying molecular mechanisms shaping tumour evolution during treatment are incompletely understood. Genomic profiling of patient tumours has implicated apolipoprotein B messenger RNA editing catalytic polypeptide-like (APOBEC) cytidine deaminases in tumour evolution; however, their role during therapy and the development of acquired drug resistance is undefined. Here we report that lung cancer targeted therapies commonly used in the clinic can induce cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Therapy-induced A3A promotes the formation of double-strand DNA breaks, increasing genomic instability in drug-tolerant persisters. Deletion of A3A reduces APOBEC mutations and structural variations in persister cells and delays the development of drug resistance. APOBEC mutational signatures are enriched in tumours from patients with lung cancer who progressed after extended responses to targeted therapies. This study shows that induction of A3A in response to targeted therapies drives evolution of drug-tolerant persister cells, suggesting that suppression of A3A expression or activity may represent a potential therapeutic strategy in the prevention or delay of acquired resistance to lung cancer targeted therapy.
  6. Nature. 2023 Jul 05.
    Keywords:  Cancer; Cosmology; Evolution; Genetics; Synthetic biology