Ethylmalonic Encephalopathy 1 Protein Is Increased in Colorectal Adenocarcinoma

Abstract

Background/Aim: Ethylmalonic encephalopathy 1 protein (ETHE1) plays an important role in sulfide catabolism and polysulfide formation. As sulfides and polysulfides have recently been identified as playing important roles in cancer, we hypothesized that ETHE1 expression would be increased in colon cancer. Materials and Methods: We used tissue microarray analysis to compare ETHE1 expression in benign colonic epithelium compared to colonic adenocarcinoma. In total, 26 benign colonic epithelial samples were compared to 122 cases of colonic adenocarcinomas. Results: Compared to benign colonic epithelium, ETHE1 expression was significantly increased (~two-fold) in colonic adenocarcinoma. Additionally, this expression increased with increasing colon cancer tumor grades. Conclusion: ETHE1 expression is increased in colon cancer compared to benign colonic epithelium. These data, combined with previous studies, suggest that ETHE1 may contribute to colon carcinogenesis by promoting tumor cell bioenergetics and polysulfide formation.Ethylmalonic encephalopathy 1 protein (ETHE1), also known as sulfur dioxygenase, is located on chromosome 19q13 and encodes a mettallo β-lactamase family enzyme containing a mononuclear iron center (1-4). Loss-of-function ETHE1 mutations are associated with ethylmalonic encephalopathy, a rare infantile autosomal recessive metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels, characterized by psychomotor regression with generalized hypotonia, evolving into tetraparesis, dystonia, and subsequent global neurological failure and death in the first decade (3-5). Patients with ethylmalonic encephalopathy exhibit lactic acidemia, elevated urine ethylmalonic and methylsuccinic acids, and low skeletal muscle mitochondrial respiratory complex IV activity (3-5).ETHE1 functions in the mitochondrial matrix oxidizing sulfides to sulfate or sulfate esters, and taurine, through the sequential actions of sulfide: quinone oxidoreductase, ETHE1, and rhodanese (6). Specifically, ETHE1 detoxifies/oxidizes hydrogen sulfide (H2S) and glutathione polysulfides (glutathione-persulfide, -trisulfide, and -tetrasulfide), but not cysteine-or homocysteine-persulfides/polysulfides (6-8). Interestingly, ETHE1 also exhibits cysteine protein polysulfidation activities. ETHE1 persulfide dioxygenase and polysulfidation activities are dependent on Cys247 polysulfidation and replacement of the Cys247 with serine ablates both enzymatic activities (8). The enzymes that synthesize H2S, cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST), also function in polysulfide synthesis; suggesting that these enzymes and ETHE1 function together to regulate cellular polysulfide levels (8-10).Recently, one or more of the enzymes that synthesize H2S have been found to be increased in many different human malignancies, with one study of oral squamous cell carcinoma also showing significantly increased tumor H2S levels (11-13). Additionally, there is recent evide...

ETHE1 Accelerates Triple-Negative Breast Cancer Metastasis by Activating GCN2/eIF2α/ATF4 Signaling

“…Although ETHE1 plays a key role in ethylmalonic encephalopathy, its role in human cancer is poorly understood. To date, only a few studies have indicated the role of ETHE1 in tumorigenesis of colorectal cancer [14,15]. In this study, we demonstrated that ETHE1 was upregulated in TNBC.…”

“…Despite its pivotal role in ethylmalonic encephalopathy, whether dysregulation of ETHE1 is implicated in human cancer is poorly understood. Emerging evidence shows that ETHE1 is upregulated in colorectal adenocarcinoma compared with benign colonic epithelium and it may also contribute to colorectal tumorgenicity [14,15]. Additionally, ETHE1 forms a biomarker panel with H-Ras and p53 to diagnose early-stage lung cancer [16].…”

A Comprehensive Prognostic Model for Colon Adenocarcinoma Depending on Nuclear-Mitochondrial-Related Genes

“… 46 Ozluk et al suggested that ETHE1 may promote the development of colon cancer and participate in sulfide catabolism and polysulfide formation by promoting the bioenergetics of tumor cells and the formation of polysulfide. 47 ATP8A2 and ETHE1 were also identified as prognostic biomarkers in lung adenocarcinoma. 48 Moreover, low expression of ATP8A2 is related to poor prognosis in lung adenocarcinoma, 49 and abnormally methylated ATP8A2 was found in various cancers.…”

Implications of hydrogen sulfide in colorectal cancer: Mechanistic insights and diagnostic and therapeutic strategies

“…Moreover, elevated expression of SQR and ETHE1 was observed in all six CRC cell lines (HT29, LoVo, Caco-2, RKO, DLD-1, and HCT116), compared to the non-cancerous colon cell line HCEC [ 1 ]. It has been noted that ETHE1 expression is significantly increased in CRC and increases with CRC tumor grade compared to benign colonic epithelium [ 119 ]. It has also been found that human colon cancer cells HT-29 Glc (−/+) have an enhanced ability to oxidize sulfide when differentiated spontaneously or induced by butyrate [ 75 ].…”