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


The cover for issue 40 of Oncotarget features Figure 7, "Model figure of ETHE1 roles in FAP," by Witherspoon, et al.

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, oxidative phosphorylation, and mitochondrial biogenesis in colorectal cancer cell lines, thereby depleting H2S which relieved the inhibition of phosphodiesterase, and increased adenosine monophosphate levels.

Dr. Steven Lipkin and Dr. Levy Kopelovich (jointly led the study) from the Department of Medicine at the Weill Cornell College of Medicine in New York, NY, USA "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."

A recent proteomic study showed that phenotypically normal epithelial cells from the colonic crypts of FAP patients, referred to as one-hit cells, when compared to normal colon epithelial cells, revealed a significant increase of the Ethylmalonic encephalopathy protein 1 which, represented the highest increase in expression among all proteins identified.

Figure 7: Model figure of ETHE1 roles in FAP.

Figure 7: Model figure of ETHE1 roles in FAP. Overexpression of ETHE1 prevents H2S mediated inhibition of PDE, increasing AMPKp activation of Sirt1 and subsequent induction of PGC1α, increasing CRC mitochondrial OXPHOS, proliferation, angiogenesis and tumorigenicity.

Here, we focused on the colon since ETHE1 is highly expressed in normal colorectal epithelium wherein it modulates the accumulation of toxic endogenous H2S generated by colonic microbiota, dietary sulfur containing compounds and endogenous cellular H2S produced by cystathionine beta-synthase.

We found abnormal expression of ETHE1 and increased mitochondria density in phenotypically normal APC+/- FAP intact colorectal mucosa.

Furthermore, using constitutively expressed ETHE1 in CRC cells we identified novel mechanisms that link augmented ETHE1 expression with aerobic glycolysis and mitochondria biogenesis.

Overall our studies provide new insights into the mechanistic role of elevated ETHE1 expression levels during CRC tumorigenesis in phenotypically normal one-hit FAP colon, highlighting the utility of the one-hit model in heritable cancers to facilitate the discovery of potential biomarkers/targets, early during CRC progression.

The Lipkin/Kopelovich concluded, Our findings here confirm these original findings in additional FAP colon biospecimens and extend our current mechanistic understanding of the role of ETHE1 in FAP CRC tumorigenesis with both in vitro and in vivo studies, leading to the following salient conclusions: First, because ETHE1 promotes CRC cell growth, and is upregulated in phenotypically normal APC+/- FAP colon epithelium, high ETHE1 levels may be useful as an early biomarker of CRC premalignant risk.

Second, ETHE1 may be a potential chemoprevention target for FAP and high-risk sporadic CRC patients.

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DOI - https://doi.org/10.18632/oncotarget.26958

Full text - https://www.oncotarget.com/article/26958/text/

Correspondence to - Steven Lipkin - [email protected] and Levy Kopelovich - [email protected]

Keywords - familial adenomatous polyposis, ethylmalonic encephalopathy 1, mitochondrial bioenergetics, aerobic glycolysis, colorectal cancer

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