ETHE1 overexpression promotes SIRT1 and PGC1α mediated aerobic glycolysis, oxidative phosphorylation, mitochondrial biogenesis and colorectal cancer
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Mavee Witherspoon1,*, Davinder Sandu2,*, Changyuan Lu2, Kehui Wang3, Robert Edwards3, Anthony Yeung4, Ozkan Gelincik1, Giovanni Manfredi5, Steven Gross2, Levy Kopelovich1,** and Steven Lipkin1
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
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
Ethylmalonic Encephalopathy Protein 1 (ETHE1) is a sulfur dioxygenase that regulates cellular H2S 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 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 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.
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