Metabolic control of primed human pluripotent stem cell fate and function by the miR-200c–SIRT2 axis

Abstract

A hallmark of cancer cells is the metabolic switch from oxidative phosphorylation (OXPHOS) to glycolysis, a phenomenon referred to as the ‘Warburg effect’, which is also observed in primed human pluripotent stem cells (hPSCs). Here, we report that downregulation of SIRT2 and upregulation of SIRT1 is a molecular signature of primed hPSCs and that SIRT2 critically regulates metabolic reprogramming during induced pluripotency by targeting glycolytic enzymes including aldolase, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase, and enolase. Remarkably, knockdown of SIRT2 in human fibroblasts resulted in significantly decreased OXPHOS and increased glycolysis. In addition, we found that miR-200c-5p specifically targets SIRT2, downregulating its expression. Furthermore, SIRT2 overexpression in hPSCs significantly affected energy metabolism, altering stem cell functions such as pluripotent differentiation properties. Taken together, our results identify the miR-200c–SIRT2 axis as a key regulator of metabolic reprogramming (Warburg-like effect), via regulation of glycolytic enzymes, during human induced pluripotency and pluripotent stem cell function.

Dichloroacetic acid (DCA) synergizes with the SIRT2 inhibitor Sirtinol and AGK2 to enhance anti-tumor efficacy in non-small cell lung cancer

“…Seong-Hoon et al found that SIRT2-lacking cells exhibited a higher extent of glycolytic phenotype in mammary tumor cells by targeting PKM2, 34 Young et al found that knockdown of SIRT2 resulted in significantly decreased OXPHOS and increased glycolysis by targeting enolase, GAPDH and aldolase in human fibroblasts. 35 In contrary, Xu et al found that SIRT2 could enhance glycolysis in A549 and MEF cells by targeting PGAM2. 3,36 Wang et al revealed that SIRT2 could inhibit oxidative stress by activating G6PD 2 in HEK293T cells.…”

Non-coding RNAs: long non-coding RNAs and microRNAs in endocrine-related cancers

“…Many ncRNAs appear to be involved in rapid cell stress responses and may be involved in anterograde and retrograde signaling between the nucleus and mitochondria to regulate energy homeostasis and apoptosis. For example, miRNAs appear to provide anterograde regulation of mitochondrial function, apoptosis, and cancer cell metabolism (Cha, et al 2017;Duarte et al 2015). However, although mitochondrial dysfunction is a hallmark of cancer, the role of ncRNAs in the mitochondrial unfolded protein response (UPRmt) in cancer (reviewed in (Kenny and Germain 2017)) remains to be examined.…”

Scarless Enriched selection of Genome edited Human Pluripotent Stem Cells Using Induced Drug Resistance

“…3D and S1E), fluorescence-based competition assay with WT control (Fig. 3E) (Cha et al, 2017), and in vitro and in vivo differentiation potentials (Figs. 2F and G).…”