Fatty acid synthase (FASN) catalyzes the synthesis of long chain saturated fatty acids and is overexpressed during prostatic tumorigenesis, where it is the therapeutic target in several ongoing trials. However, the mechanism of FASN upregulation in prostate cancer remains unclear. Here, we examine FASN gene CpG methylation pattern by InfiniumEPIC profiling and whole genome bisulfite sequencing (WGBS) across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing to FASN protein expression as measured by digitally quantified immunohistochemistry assay and reverse phase protein array analysis or FASN gene expression. We demonstrate that the FASN gene body is hypomethylated and overexpressed in primary prostate tumors compared to benign tissue, and FASN gene methylation is significantly inversely correlated with FASN protein or gene expression in both primary and metastatic prostate cancer. Primary prostate tumors with ERG gene rearrangement have increased FASN expression and we find evidence of FASN hypomethylation in this context. FASN expression is also significantly increased in prostate tumors from carriers of the germline HOXB13 G84E mutation compared to matched controls, consistent with a report that HOXB13 may contribute to epigenetic regulation of FASN in vitro. However, in contrast to previous studies, we find no significant association of FASN expression or methylation with self-identified race in models that include ERG status across two independent primary tumor cohorts. Taken together, these data support a potential epigenetic mechanism for FASN regulation in the prostate which may be relevant for selecting patients responsive to FASN inhibitors.
Cancer research communications. 2023 Dec 19 [Epub ahead of print]
Oluwademilade O Dairo, Lia DePaula Oliveira, Ethan Schaffer, Thiago Vidotto, Adrianna A A Mendes, Jiayun Lu, Sophie Vo Huynh, Jessica L Hicks, Adam G Sowalsky, Angelo M De Marzo, Corinne E Joshu, Brian Hanratty, Karen S Sfanos, William B Isaacs, Michael C Haffner, Tamara L Lotan
Johns Hopkins University School of Medicine, Baltimore, MD, United States., Johns Hopkins University, Baltimore, Maryland, United States., Johns Hopkins University, Baltimore, MD, United States., Johns Hopkins University, United States., National Cancer Institute, Bethesda, MD, United States., Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States., Fred Hutchinson Cancer Research Center, Seattle, WA, United States., Fred Hutchinson Cancer Research Center, Seattle, United States.