title: Downregulation of acetyl-CoA synthetase 2 is a metabolic hallmark of tumor progression and aggressiveness in colorectal carcinoma.
abstract: Acetyl-CoA synthetase-2 is an emerging key enzyme for cancer metabolism, which supplies acetyl-CoA for tumor cells by capturing acetate as a carbon source under stressed conditions. However, implications of acetyl-CoA synthetase-2 in colorectal carcinoma may differ from other malignancies, because normal colonocytes use short-chain fatty acids as an energy source, which are supplied by fermentation of the intestinal flora. Here we analyzed acetyl-CoA synthetase-2 mRNA expression by reverse-transcription quantitative PCR in paired normal mucosa and tumor tissues of 12 colorectal carcinomas, and subsequently evaluated acetyl-CoA synthetase-2 protein expression by immunohistochemistry in 157 premalignant colorectal lesions, including 60 conventional adenomas and 97 serrated polyps, 1,106 surgically resected primary colorectal carcinomas, and 23 metastatic colorectal carcinomas in the liver. In reverse-transcription quantitative PCR analysis, acetyl-CoA synthetase-2 mRNA expression was significantly decreased in tumor tissues compared with corresponding normal mucosa tissues. In acetyl-CoA synthetase-2 immunohistochemistry analysis, all 157 colorectal polyps showed moderate-to-strong expression of acetyl-CoA synthetase-2. However, cytoplasmic acetyl-CoA synthetase-2 expression was downregulated (acetyl-CoA synthetase-2 low expression) in 771 (69.7%) of 1,106 colorectal carcinomas and 21 (91.3%) of 23 metastatic lesions. The colorectal carcinomas with acetyl-CoA synthetase-2-low expression were significantly associated with advanced TNM stage, poor differentiation, and frequent tumor budding. Regarding the molecular aspect, acetyl-CoA synthetase-2-low expression exhibited a tendency of frequent KRT7 expression and decreased KRT20 and CDX2 expression. In survival analysis, acetyl-CoA synthetase-2-low expression was an independent prognostic factor for poor 5-year progression-free survival (hazard ratio, 1.39; 95% confidence interval, 1.08-1.79; P=0.01). In conclusion, these findings suggest that downregulation of acetyl-CoA synthetase-2 expression is a metabolic hallmark of tumor progression and aggressive behavior in colorectal carcinoma.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Pathology, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Jeong Mo
authors.initials: JM
authors.lastname: Bae
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jung Ho
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hyeon Jeong
authors.initials: HJ
authors.lastname: Oh
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Park
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Tae Hun
authors.initials: TH
authors.lastname: Lee
authors.affiliation: Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.|Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Gyeong Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism*; D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D011379:Prognosis
chemical_list: D000106:Acetate-CoA Ligase