FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-Genomic Features of Prostate Cancer.
Oluwademilade O DairoLia DePaula OliveiraEthan D SchafferThiago VidottoAdrianna A A MendesJiayun LuSophie Vo HuynhJessica L HicksAdam G SowalskyAngelo M DeMarzoCorrine E JoshuBrian HanrattyKaren S SfanosWilliam B IsaacsMichael C HaffnerTamara L LotanPublished in: Cancer research communications (2023)
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.
Keyphrases
- prostate cancer
- gene expression
- fatty acid
- dna methylation
- genome wide
- radical prostatectomy
- poor prognosis
- copy number
- small cell lung cancer
- squamous cell carcinoma
- magnetic resonance
- magnetic resonance imaging
- binding protein
- benign prostatic hyperplasia
- signaling pathway
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- computed tomography
- high throughput
- genome wide identification
- small molecule
- transcription factor
- contrast enhanced
- drug delivery
- patient reported outcomes
- climate change
- protein protein
- case control