bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒10‒17
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Oncogene. 2021 Oct 14.
      Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.
  2. Trends Genet. 2021 Oct 06. pii: S0168-9525(21)00270-5. [Epub ahead of print]
      Histone lactylation and acetylation compete for epigenetic modification of lysines and mark the levels of lactates and acetyl-CoA. Whether pyruvate is committed to lactate or acetyl-CoA generation as the outlet of glycolysis determines cell fate towards malignancy or not. Taking control over the glycolytic switch as marked by lactylation suggests novel therapeutic opportunities against cancers.
    Keywords:  acetylation; epigenetic mark; glycolysis switch; lactylation
  3. Molecules. 2021 Sep 28. pii: 5883. [Epub ahead of print]26(19):
      O-GlcNAcylation is a nutrient-driven post-translational modification known as a metabolic sensor that links metabolism to cellular function. Recent evidences indicate that the activation of O-GlcNAc pathway is a potential pro-survival pathway and that acute enhancement of this response is conducive to the survival of cells and tissues. 2-(4-Methoxyphenyl)ethyl-2-acetamido-2-deoxy-β-d-pyranoside (SalA-4g), is a salidroside analogue synthesized in our laboratory by chemical structure-modification, with a phenyl ring containing a para-methoxy group and a sugar ring consisting of N-acetylglucosamine. We have previously shown that SalA-4g elevates levels of protein O-GlcNAc and improves neuronal tolerance to ischemia. However, the specific target of SalA-4g regulating O-GlcNAcylation remains unknown. To address these questions, in this study, we have focused on mitochondrial network homeostasis mediated by O-GlcNAcylation in SalA-4g's neuroprotection in primary cortical neurons under ischemic-like conditions. O-GlcNAc-modified mitochondria induced by SalA-4g demonstrated stronger neuroprotection under oxygen glucose deprivation and reoxygenation stress, including the improvement of mitochondrial homeostasis and bioenergy, and inhibition of mitochondrial apoptosis pathway. Blocking mitochondrial protein O-GlcNAcylation with OSMI-1 disrupted mitochondrial network homeostasis and antagonized the protective effects of SalA-4g. Collectively, these data demonstrate that mitochondrial homeostasis mediated by mitochondrial protein O-GlcNAcylation is critically involved in SalA-4g neuroprotection.
    Keywords:  2-(4-methoxyphenyl)ethyl-2-acetamido-2-deoxy-b-d-pyranoside; O-GlcNAcylation; cellular bioenergetics; mitochondrial homeostasis; neuroprotection; oxygen glucose deprivation/reoxygenation stress
  4. Cell Metab. 2021 Oct 06. pii: S1550-4131(21)00432-0. [Epub ahead of print]
      Pluripotent stem cells model certain features of early mammalian development ex vivo. Medium-supplied nutrients can influence self-renewal, lineage specification, and earliest differentiation of pluripotent stem cells. However, which specific nutrients support these distinct outcomes, and their mechanisms of action, remain under active investigation. Here, we evaluate the available data on nutrients and their metabolic conversion that influence pluripotent stem cell fates. We also discuss key questions open for investigation in this rapidly expanding area of increasing fundamental and practical importance.
    Keywords:  development; differentiation; fate; metabolism; nutrients; pluripotent stem cell
  5. J Genet Genomics. 2021 Oct 11. pii: S1673-8527(21)00321-0. [Epub ahead of print]
      Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years. However, the mechanisms of multi-level regulation of cell fate determination remain unclear. Recently we have proposed an Epigenome-Metabolome-Epigenome (E-M-E) signaling cascade model to describe the crossover cooperation during mouse somatic cell reprogramming. In this review, we summarize the broad roles of E-M-E signaling cascade in different cell biological processes including cell differentiation and dedifferentiation, cell specialization, cell proliferation and cell pathological processes. Precise E-M-E signaling cascades are critical in these cell biological processes, and it is of worth to explore each step of E-M-E signaling cascade. E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multi-level regulation of cell biological processes.
    Keywords:  Cell biological processes; Chromatin; Epigenome; Mabolome; Signaling cascade