bims-ectoca Biomed News
on Epigenetic control of tolerance in cancer
Issue of 2024–01–14
five papers selected by
Ankita Daiya, Birla Institute of Technology and Science



  1. Nat Chem Biol. 2024 Jan 10.
      Biomolecular condensates have been proposed to mediate cellular signaling transduction. However, the mechanism and functional consequences of signal condensates are not well understood. Here we report that LATS2, the core kinase of the Hippo pathway, responds to F-actin cytoskeleton reduction and forms condensates. The proline-rich motif (PRM) of LATS2 mediates its condensation. LATS2 partitions with the main components of the Hippo pathway to assemble a signalosome for LATS2 activation and for its stability by physically compartmentalizing from E3 ligase FBXL16 complex-dependent degradation, which in turn mediates yes-associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) recruitment and inactivation. This oncogenic FBXL16 complex blocks LATS2 condensation by binding to the PRM region to promote its degradation. Disruption of LATS2 condensation leads to tumor progression. Thus, our study uncovers that the signalosomes assembled by LATS2 condensation provide a compartmentalized and reversible platform for Hippo signaling transduction and protein stability, which have potential implications in cancer diagnosis and therapeutics.
    DOI:  https://doi.org/10.1038/s41589-023-01516-x
  2. Free Radic Biol Med. 2024 Jan 04. pii: S0891-5849(24)00003-0. [Epub ahead of print]
      Pancreatic ductal adenocarcinoma (PDAC) has extremely poor prognosis, with a 5-year survival rate of approximately 11 %. Yes-associated protein (YAP) is a major downstream effector of the Hippo-YAP pathway and plays a pivotal role in regulation of cell proliferation and organ regeneration and tumorigenesis. Activation of YAP signaling has been associated with PDAC progression and drug resistance. Verteporfin (VP) is a photosensitizer used for photodynamic therapy and previous work showed that it can function as a YAP inhibitor. The efficacy of VP on human cancer are being tested in several trials. In this study, we examined the effect of VP on reactive oxygen species (ROS) and lipid peroxidation in pancreatic cancer cells, by using fluorescent molecular probes and by measuring the levels of malondialdehyde, a metabolic byproduct and marker of lipid peroxidation. We found that VP causes rapid increase of both overall ROS and lipid peroxide levels, independent of light activation. These effects were not dependent on YAP, as knockdown of YAP did not cause ROS or lipid peroxidation or enhance VP-induced ROS production. Temoporfin, another photodynamic drug, did not show similar activities. In addition, VP treatment led to loss of cell membrane integrity and reduction of viability. Notably, the activity of VP to induce lipid peroxidation was neutralized by ferroptosis inhibitors ferrostatin-1 or liproxstatin-1. VP treatment also reduced the levels of glutathione peroxidase 4 (GPX4), an enzyme that protects against lipid peroxidation. These results indicate that VP can induce lipid peroxidation and ferroptosis in the absence of light activation. Our findings reveal a novel mechanism by which VP inhibits tumor growth and provide insights into development of new therapeutic strategies for the treatment of pancreatic cancer.
    Keywords:  Ferroptosis; Lipid peroxidation; Pancreatic cancer; Reactive oxygen species; Verteporfin
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.003
  3. Cells. 2024 Jan 02. pii: 96. [Epub ahead of print]13(1):
      Extracellular biophysical properties have particular implications for a wide spectrum of cellular behaviors and functions, including growth, motility, differentiation, apoptosis, gene expression, cell-matrix and cell-cell adhesion, and signal transduction including mechanotransduction. Cells not only react to unambiguously mechanical cues from the extracellular matrix (ECM), but can occasionally manipulate the mechanical features of the matrix in parallel with biological characteristics, thus interfering with downstream matrix-based cues in both physiological and pathological processes. Bidirectional interactions between cells and (bio)materials in vitro can alter cell phenotype and mechanotransduction, as well as ECM structure, intentionally or unintentionally. Interactions between cell and matrix mechanics in vivo are of particular importance in a variety of diseases, including primarily cancer. Stiffness values between normal and cancerous tissue can range between 500 Pa (soft) and 48 kPa (stiff), respectively. Even the shear flow can increase from 0.1-1 dyn/cm2 (normal tissue) to 1-10 dyn/cm2 (cancerous tissue). There are currently many new areas of activity in tumor research on various biological length scales, which are highlighted in this review. Moreover, the complexity of interactions between ECM and cancer cells is reduced to common features of different tumors and the characteristics are highlighted to identify the main pathways of interaction. This all contributes to the standardization of mechanotransduction models and approaches, which, ultimately, increases the understanding of the complex interaction. Finally, both the in vitro and in vivo effects of this mechanics-biology pairing have key insights and implications for clinical practice in tumor treatment and, consequently, clinical translation.
    Keywords:  EMT; cancer cells; cancer-associated fibroblasts (CAFs); cell mechanics; extracellular matrix (ECM) remodeling; fibronectin; immune cells; mechanosensing; plasticity
    DOI:  https://doi.org/10.3390/cells13010096
  4. NAR Genom Bioinform. 2024 Mar;6(1): lqad112
      Altered open chromatin regions, impacting gene expression, is a feature of some human disorders. We discovered it is possible to detect global changes in genomically-related adjacent gene co-expression within single cell RNA sequencing (scRNA-seq) data. We built a software package to generate and test non-randomness using 'Brooklyn plots' to identify the percent of genes significantly co-expressed from the same chromosome in ∼10 MB intervals across the genome. These plots establish an expected low baseline of co-expression in scRNA-seq from most cell types, but, as seen in dilated cardiomyopathy cardiomyocytes, altered patterns of open chromatin appear. These may relate to larger regions of transcriptional bursting, observable in single cell, but not bulk datasets.
    DOI:  https://doi.org/10.1093/nargab/lqad112
  5. Cell Mol Life Sci. 2024 Jan 12. 81(1): 26
      Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.
    Keywords:  Epigenetic modifications; Mitochondria; Mitochondria metabolites; Senescence; Stem cell fate
    DOI:  https://doi.org/10.1007/s00018-023-05070-6