Abstract
A subset of human prostate cancer exhibits increased de novo synthesis of fatty acids, but the molecular driver(s) of this metabolic abnormality remains obscure. This study demonstrates a novel metabolic function of c-Myc (Myc) in regulation of fatty acid synthesis. The role of Myc in regulation of fatty acid synthesis was investigated by: (a) interrogation of the prostate cancer The Cancer Genome Atlas (TCGA) dataset, (b) chromatin immunoprecipitation, and (c) determination of the expression of fatty acid synthesis enzymes and targeted metabolomics using a mouse model and human specimens. The expression of MYC was positively associated with that of key fatty acid synthesis genes including ACLY, ACC1, and FASN in prostate cancer TCGA dataset. Chromatin immunoprecipitation revealed Myc occupancy at the promoters of ACLY, ACC1, and FASN. Prostate-specific overexpression of Myc in Hi-Myc transgenic mice resulted in overexpression of ACLY, ACC1, and FASN proteins in neoplastic lesions and increased circulating levels of total free fatty acids. Targeted metabolomics confirmed increased circulating levels of individual fatty acids in the plasma of Hi-Myc mice and human subjects when compared to corresponding controls. Immunohistochemistry also revealed a positive and statistically significant association in expression of Myc with that of ACC1 in human prostate adenocarcinoma specimens. We propose that Myc-regulated fatty acid synthesis is a valid target for therapy and/or prevention of prostate cancer.