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

Abstract

// Mavee Witherspoon 1 , * , Davinder Sandu 2 , * , Changyuan Lu 2 , Kehui Wang 3 , Robert Edwards 3 , Anthony Yeung 4 , Ozkan Gelincik 1 , Giovanni Manfredi 5 , Steven Gross 2 , Levy Kopelovich 1 , ** and Steven Lipkin 1 1 Department of Medicine, Weill Cornell College of Medicine, New York, NY, USA 2 Department of Pharmacology, Weill Cornell College of Medicine, New York, NY, USA 3 Department of Pathology and Laboratory Medicine, University of Irvine School of Medicine, Irvine, CA, USA 4 Fox Chase Cancer Center, Philadelphia, PA, USA 5 Department of Neurology, Weill Cornell College of Medicine, New York, NY, USA * These authors contributed equally to this work ** Jointly led the study Correspondence to: Steven Lipkin, email: stl2012@med.cornell.edu Levy Kopelovich, email: kopelovichl@gmail.com Keywords: familial adenomatous polyposis; ethylmalonic encephalopathy 1; mitochondrial bioenergetics; aerobic glycolysis; colorectal cancer Received: January 16, 2018     Accepted: April 21, 2019     Published: June 18, 2019 ABSTRACT Ethylmalonic Encephalopathy Protein 1 ( ETHE1 ) is a sulfur dioxygenase that regulates cellular H 2 S levels. We previously demonstrated a significant increase of ETHE1 expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of ETHE1 expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of ETHE1 increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting H 2 S 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 ETHE1 reduced PDE activity, AMPKp/SIRT1/PGC1α levels and mitochondrial biogenesis. Constitutive expression of ETHE1 accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth in vivo . Overall, our data nominate elevated ETHE1 expression levels as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.