Abstract
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.
Highlights
The discovery of tumor suppressor genes (TSGs) and their singular role in the etiology of heritable cancers presents the opportunity to study early biomarkers and potential targets during cancer progression [1]
We found that constitutive expression of Encephalopathy Protein 1 (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
Yeung et al demonstrated that phenotypically normal, non-transformed adenomatous polyposis coli (APC) "single-hit" cells in Familial Adenomatous Polyposis (FAP) epithelium showed the highest differential increase in ETHE1 levels among all proteins identified compared to normal colon epithelial cells from control subjects [16]
Summary
The discovery of tumor suppressor genes (TSGs) and their singular role in the etiology of heritable cancers presents the opportunity to study early biomarkers and potential targets during cancer progression [1]. We investigated gene expression patterns of phenotypically normal “one-hit” cells before they become hemizygous or www.oncotarget.com homozygous for the inherited mutant TSG that promotes tumor formation in hereditary cancers This approach enables discovery of biomarkers and molecular targets in clinically-identifiable pre-neoplastic lesions such as polyposis of the colon, wherein numerous lesions appear before progression to adenocarcinomas [1,2,3,4]. The high rate of somatic APC mutations in sporadic colorectal cancer is consistent with inactivation of the APC protein playing a critical role in the initiation of colorectal cancers [8] This highlights the need to improve our understanding of events that occur during the transition of normal colon mucosa to cancer including development of early biomarkers and potential targets to prevent/treat FAP and other cohorts at high risk of CRC [9,10,11,12,13,14,15]
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