ETHE1 overexpression promotes SIRT1 and PGC1α mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer

Abstract

Ethylmalonic Encephalopathy Protein 1 (<i>ETHE1</i>) is a sulfur dioxygenase that regulates cellular H₂S levels. We previously demonstrated a significant increase of <i>ETHE1</i> expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of <i>ETHE1</i> expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of <i>ETHE1</i> increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting H₂S which relieved the inhibition of phosphodiesterase (PDE), and increased adenosine monophosphate (AMP) levels. This led to activation of the energy sensing AMP-activated protein kinase (AMPKp), Sirtuin1 (SIRT1) and peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), a master regulator of mitochondrial biogenesis. By contrast, shRNA silencing of <i>ETHE1</i> reduced PDE activity, AMPKp/SIRT1/PGC1α levels and mitochondrial biogenesis. Constitutive expression of <i>ETHE1</i> accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth <i>in vivo</i>. Overall, our data nominate elevated <i>ETHE1 expression levels</i> as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.