bims-ectoca 2024-08-11 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024–08–11
five papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance.
Mechanical remodeling of nuclear biomolecular condensates.
Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.
Oxidative stress-induced YAP1 expression is regulated by NCE102, CDA2, and BCS1.
Kinetic Trajectories of Glucose Uptake in Single Cancer Cells Reveal a Drug-Induced Cell-State Change Within Hours of Drug Treatment.

Mol Cell. 2024 Jul 26. pii: S1097-2765(24)00582-3. [Epub ahead of print]

Nucleosome remodeler exclusion by histone deacetylation enforces heterochromatic silencing and epigenetic inheritance.

Rakesh Kumar Sahu, Jothy Dhakshnamoorthy, Shweta Jain, Hernan Diego Folco, David Wheeler, Shiv I S Grewal.

  Heterochromatin enforces transcriptional gene silencing and can be epigenetically inherited, but the underlying mechanisms remain unclear. Here, we show that histone deacetylation, a conserved feature of heterochromatin domains, blocks SWI/SNF subfamily remodelers involved in chromatin unraveling, thereby stabilizing modified nucleosomes that preserve gene silencing. Histone hyperacetylation, resulting from either the loss of histone deacetylase (HDAC) activity or the direct targeting of a histone acetyltransferase to heterochromatin, permits remodeler access, leading to silencing defects. The requirement for HDAC in heterochromatin silencing can be bypassed by impeding SWI/SNF activity. Highlighting the crucial role of remodelers, merely targeting SWI/SNF to heterochromatin, even in cells with functional HDAC, increases nucleosome turnover, causing defective gene silencing and compromised epigenetic inheritance. This study elucidates a fundamental mechanism whereby histone hypoacetylation, maintained by high HDAC levels in heterochromatic regions, ensures stable gene silencing and epigenetic inheritance, providing insights into genome regulatory mechanisms relevant to human diseases.

Keywords:  H3K9me3; RSC; SWI/SNF; chromatin remodeling; epigenetic inheritance; gene silencing; heterochromatin; histone deacetylation; histone modifications; read-write

DOI:  https://doi.org/10.1016/j.molcel.2024.07.006
Physiology (Bethesda). 2024 Aug 07.

Mechanical remodeling of nuclear biomolecular condensates.

Giulia Soggia, Yasmin ElMaghloob, Annie-Kermen Boromangnaeva, Adel Al Jord.

  Organism health relies on cell proliferation, migration, and differentiation. These universal processes depend on cytoplasmic reorganization driven notably by the cytoskeleton and its force-generating motors. Their activity generates forces that mechanically agitate the cell nucleus and its interior. New evidence from reproductive cell biology revealed that these cytoskeletal forces can be tuned to remodel nuclear membrane-less compartments, known as biomolecular condensates, and regulate their RNA processing function for the success of subsequent cell division that is critical for fertility. Both cytoskeletal and nuclear condensate reorganization are common to numerous physiological and pathological contexts, raising the possibility that mechanical remodeling of nuclear condensates may be a much broader mechanism regulating their function. Here, we review this newfound mechanism of condensate remodeling and venture into contexts of health and disease where it may be relevant, with a focus on reproduction, cancer, and premature aging.

Keywords:  Aging; Biomolecular Condensates; Cancer; Nucleus; Oocytes

DOI:  https://doi.org/10.1152/physiol.00027.2024
Nat Commun. 2024 Aug 08. 15(1): 6777

Metabolic and transcriptomic reprogramming during contact inhibition-induced quiescence is mediated by YAP-dependent and YAP-independent mechanisms.

Soeun Kang, Maciek R Antoniewicz, Nissim Hay.

Metabolic rewiring during the proliferation-to-quiescence transition is poorly understood. Here, using a model of contact inhibition-induced quiescence, we conducted 13C-metabolic flux analysis in proliferating (P) and quiescent (Q) mouse embryonic fibroblasts (MEFs) to investigate this process. Q cells exhibit reduced glycolysis but increased TCA cycle flux and mitochondrial respiration. Reduced glycolytic flux in Q cells correlates with reduced glycolytic enzyme expression mediated by yes-associated protein (YAP) inhibition. The increased TCA cycle activity and respiration in Q cells is mediated by induced mitochondrial pyruvate carrier (MPC) expression, rendering them vulnerable to MPC inhibition. The malate-to-pyruvate flux, which generates NADPH, is markedly reduced by modulating malic enzyme 1 (ME1) dimerization in Q cells. Conversely, the malate dehydrogenase 1 (MDH1)-mediated oxaloacetate-to-malate flux is reversed and elevated in Q cells, driven by high mitochondrial-derived malate levels, reduced cytosolic oxaloacetate, elevated MDH1 levels, and a high cytoplasmic NAD+/NADH ratio. Transcriptomic analysis revealed large number of genes are induced in Q cells, many of which are associated with the extracellular matrix (ECM), while YAP-dependent and cell cycle-related genes are repressed. The results suggest that high TCA cycle flux and respiration in Q cells are required to generate ATP and amino acids to maintain de-novo ECM protein synthesis and secretion.

DOI: https://doi.org/10.1038/s41467-024-51117-y
FEBS J. 2024 Aug 05.

Oxidative stress-induced YAP1 expression is regulated by NCE102, CDA2, and BCS1.

Sarah Takallou, Maryam Hajikarimlou, Mustafa Al-Gafari, Jiashu Wang, Sasi Kumar Jagadeesan, Thomas David Daniel Kazmirchuk, Christina Arnoczki, Houman Moteshareie, Kamaledin B Said, Taha Azad, Martin Holcik, Bahram Samanfar, Myron Smith, Ashkan Golshani.

  Maintaining cellular homeostasis in the face of stress conditions is vital for the overall well-being of an organism. Reactive oxygen species (ROS) are among the most potent cellular stressors and can disrupt the internal redox balance, giving rise to oxidative stress. Elevated levels of ROS can severely affect biomolecules and have been associated with a range of pathophysiological conditions. In response to oxidative stress, yeast activator protein-1 (Yap1p) undergoes post-translation modification that results in its nuclear accumulation. YAP1 has a key role in oxidative detoxification by promoting transcription of numerous antioxidant genes. In this study, we identified previously undescribed functions for NCE102, CDA2, and BCS1 in YAP1 expression in response to oxidative stress induced by hydrogen peroxide (H2O2). Deletion mutant strains for these candidates demonstrated increased sensitivity to H2O2. Our follow-up investigation linked the activity of these genes to YAP1 expression at the level of translation. Under oxidative stress, global cap-dependent translation is inhibited, prompting stress-responsive genes like YAP1 to employ alternative modes of translation. We provide evidence that NCE102, CDA2, and BCS1 contribute to cap-independent translation of YAP1 under oxidative stress.

Keywords:  IRES; gene expression; hydrogen peroxide; oxidative stress; translation regulation

DOI:  https://doi.org/10.1111/febs.17243
J Phys Chem B. 2024 Aug 08.

Kinetic Trajectories of Glucose Uptake in Single Cancer Cells Reveal a Drug-Induced Cell-State Change Within Hours of Drug Treatment.

Jungwoo Kim, Rachel H Ng, JingXin Liang, Dazy Johnson, Young Shik Shin, Arion F Chatziioannou, Michael E Phelps, Wei Wei, Raphael D Levine, James R Heath.

The development of drug resistance is a nearly universal phenomenon in patients with glioblastoma multiforme (GBM) brain tumors. Upon treatment, GBM cancer cells may initially undergo a drug-induced cell-state change to a drug-tolerant, slow-cycling state. The kinetics of that process are not well understood, in part due to the heterogeneity of GBM tumors and tumor models, which can confound the interpretation of kinetic data. Here, we resolve drug-adaptation kinetics in a patient-derived in vitro GBM tumor model characterized by the epithelial growth factor receptor (EGFR) variant(v)III oncogene treated with an EGFR inhibitor. We use radiolabeled 18F-fluorodeoxyglucose (FDG) to monitor the glucose uptake trajectories of single GBM cancer cells over a 12 h period of drug treatment. Autocorrelation analysis of the single-cell glucose uptake trajectories reveals evidence of a drug-induced cell-state change from a high- to low-glycolytic phenotype after 5-7 h of drug treatment. Information theoretic analysis of a bulk transcriptome kinetic series of the GBM tumor model delineated the underlying molecular mechanisms driving the cellular state change, including a shift from a stem-like mesenchymal state to a more differentiated, slow-cycling astrocyte-like state. Our results demonstrate that complex drug-induced cancer cell-state changes of cancer cells can be captured via measurements of single cell metabolic trajectories and reveal the extremely facile nature of drug adaptation.

DOI: https://doi.org/10.1021/acs.jpcb.4c03663