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

• Published in: Oncotarget 2019-06, Vol.10 (40), p.4004-4017
• Main Authors: Witherspoon, Mavee, Sandu, Davinder, Lu, Changyuan, Wang, Kehui, Edwards, Robert, Yeung, Anthony, Gelincik, Ozkan, Manfredi, Giovanni, Gross, Steven, Kopelovich, Levy, Lipkin, Steven
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.26958

Ethylmalonic Encephalopathy Protein 1 ( ) is a sulfur dioxygenase that regulates cellular H S levels. We previously demonstrated a significant increase of expression in "single-hit" colon epithelial cells from crypts of patients with Familial Adenomatous Polyposis (FAP). Here, we report elevated levels of expression and increased mitochondrial density occurring in-situ in phenotypically normal FAP colorectal mucosa. We also found that constitutive expression of increased aerobic glycolysis ("Warburg effect"), oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer (CRC) cell lines, thereby depleting H 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 reduced PDE activity, AMPKp/SIRT1/PGC1α levels and mitochondrial biogenesis. Constitutive expression of accelerated both CRC cell xenograft and orthotopic patient derived xenograft CRC cell growth . Overall, our data nominate elevated as a novel biomarker and potential therapeutic target for the prevention of CRC tumorigenesis.