bims-medhac Biomed News
on Metabolism dependent histone acetylation
Issue of 2020‒06‒14
two papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Toxicol Sci. 2020 Jun 11. pii: kfaa086. [Epub ahead of print]
      Chronic hexavalent chromium [Cr(VI)] exposure causes lung cancer and other types of cancer; however, the mechanism of Cr(VI) carcinogenesis remains to be clearly defined. Our recent study showed that chronic Cr(VI) exposure up-regulates the proto oncogene c-Myc expression, which contributes significantly to Cr(VI)-induced cell transformation, cancer stem cell (CSC)-like property and tumorigenesis. c-Myc is a master regulator of cancer cell abnormal metabolism and accumulating evidence suggests that metabolism dysregulation plays an important role in both cancer development and progression. However, little is known about the role of metabolism dysregulation in Cr(VI) carcinogenesis. This study was performed to investigate the potential role and mechanism of metabolism dysregulation in Cr(VI) carcinogenesis. It was found that Cr(VI)-transformed cells display glycolytic shift, which depends on the up-regulation of c-Myc. The glycolytic shift in Cr(VI)-transformed cells led to increased production of acetyl-CoA and elevation of histone acetylation. This, in turn, up-regulated the expression of an acetyl-CoA producing key enzyme ATP citrate lyase (ACLY) and c-Myc, forming a positive feedback loop between the up-regulation of c-Myc expression, glycolytic shift and increased-histone acetylation. It was further determined that glucose depletion not only reverses the glycolytic shift in Cr(VI)-transformed cells, but also significantly reduces their growth, CSC-like property and tumorigenicity. These findings indicate that glycolytic shift plays an important role in maintaining malignant phenotypes of Cr(VI)-transformed cells, suggesting that metabolism dysregulation is critically involved in Cr(VI) carcinogenesis.
    Keywords:  ATP citrate lyase; acetyl-CoA; c-Myc; cancer stem cell-like property; carcinogenesis; glycolytic shift; hexavalent chromium
  2. Elife. 2020 Jun 12. pii: e53247. [Epub ahead of print]9
      Cell-intrinsic and extrinsic signals regulate the state and fate of stem and progenitor cells. Recent advances in metabolomics illustrate that various metabolic pathways are also important in regulating stem cell fate. However, our understanding of the metabolic control of the state and fate of progenitor cells is in its infancy. Using Drosophila hematopoietic organ: lymph gland, we demonstrate that Fatty Acid Oxidation (FAO) is essential for the differentiation of blood cell progenitors. In the absence of FAO, the progenitors are unable to differentiate and exhibit altered histone acetylation. Interestingly, acetate supplementation rescues both histone acetylation and the differentiation defects. We further show that the CPT1/whd (withered), the rate-limiting enzyme of FAO, is transcriptionally regulated by Jun-Kinase (JNK), which has been previously implicated in progenitor differentiation. Our study thus reveals how the cellular signaling machinery integrates with the metabolic cue to facilitate the differentiation program.
    Keywords:  D. melanogaster; developmental biology