bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒07‒03
two papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. JCI Insight. 2022 Jun 30. pii: e155475. [Epub ahead of print]
      Developmental cardiac tissue is regenerative while operating under low oxygen. After birth, ambient oxygen is associated with cardiomyocyte cell cycle exit and regeneration. Likewise, cardiac metabolism undergoes a shift with cardiac maturation. Whether there are common regulators of cardiomyocyte cell cycle linking metabolism to oxygen tension remains unknown. The objective of the study is to determine whether mitochondrial UCP2 is a metabolic oxygen sensor regulating cardiomyocyte cell cycle. Neonatal rat ventricular myocytes (NRVMs) under moderate hypoxia showed increased cell cycle activity and UCP2 expression. NRVMs exhibited a metabolic shift towards glycolysis, reduced citrate synthase, mtDNA, ΔΨm and DNA damage/oxidative stress while loss of UCP2 reversed this phenotype. Next, WT and UCP2KO mice kept under hypoxia for 4 weeks showed significant decline in cardiac function that was more pronounced in UCP2KO animals. Cardiomyocyte cell cycle activity was reduced while fibrosis and DNA damage was significantly increased in UCP2KO animals compared to WT under hypoxia. Mechanistically, UCP2 increased acetyl-CoA levels, histone acetylation and altered chromatin modifiers linking metabolism to cardiomyocyte cell cycle under hypoxia. Here, we show a novel role for mitochondrial UCP2 as an oxygen sensor regulating cardiomyocyte cell cycle activity, acetyl-CoA levels and histone acetylation in response to moderate hypoxia.
    Keywords:  Cardiology; Cell cycle; Hypoxia; Metabolism; Uncoupling proteins
  2. Gastroenterology. 2022 Jun 28. pii: S0016-5085(22)00682-5. [Epub ahead of print]
      BACKGROUND & AIMS: Rapid deconditioning, also called cachexia, and metabolic reprogramming are two hallmarks of pancreatic cancer. ACSS2 is an acetyl-coA synthetase that contributes to lipid synthesis and epigenetic reprogramming. However, the role of ACSS2 on the non-selective macropinocytosis and cancer cachexia in pancreatic cancer remains elusive. In this study, we demonstrate that ACSS2 potentiates macropinocytosis and muscle wasting through metabolic reprogramming in pancreatic cancer.METHODS: Clinical significance of ACSS2 was analyzed using human pancreatic cancer patient samples. ACSS2 knockout cells were established utilizing CRISPR-Cas9 system. Single-cell RNA sequencing data from genetically engineered mouse models was analyzed. Macropinocytotic index was evaluated by dextran uptake assay. ChIP assay was performed to validate transcriptional activation. ACSS2 mediated tumor progression and muscle wasting were examined in orthotopic xenograft models.
    RESULTS: Metabolic stress induced ACSS2 expression, which is associated with worse prognosis in pancreatic cancer. ACSS2 knockout significantly suppressed cell proliferation in 2D and 3D models. Macropinocytosis associated genes are upregulated in tumor tissues and are correlated to worse prognosis. ACSS2 knockout inhibited macropinocytosis. We identified ZIP4 as a downstream target of ACSS2, and knockdown of ZIP4 reversed ACSS2 induced macropinocytosis. ACSS2 upregulated ZIP4 through ETV4 mediated transcriptional activation. ZIP4 induces macropinocytosis through CREB activated SDC1 and DNM2. Meanwhile, ZIP4 drives muscle wasting and cachexia via GSK3β mediated secretion of TRAIL. ACSS2 knockout attenuated muscle wasting and extended survival in orthotopic mouse models.
    CONCLUSIONS: ACSS2-mediated metabolic reprogramming activates ZIP4 pathway, and promotes macropinocytosis via SDC1/DNM2 and drives muscle wasting through GSK3β/TRAIL axis, which potentially provides additional nutrients for macropinocytosis in pancreatic cancer.
    Keywords:  Cachexia; Macropinocytosis; Metabolic Stress; Muscle Wasting