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.