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posted on 2024-01-18, 14:21 authored by Oluwademilade Dairo, Lia DePaula Oliveira, Ethan Schaffer, Thiago Vidotto, Adrianna A. Mendes, Jiayun Lu, Sophie Vo Huynh, Jessica Hicks, Adam G. Sowalsky, Angelo M. De Marzo, Corrine E. Joshu, Brian Hanratty, Karen S. Sfanos, William B. Isaacs, Michael C. Haffner, Tamara L. Lotan FASN protein expression, and to a lesser extent FASN gene methylation, is associated with ERG status in primary tumor cohort. A, FASN protein expression by immunostaining is higher in ERG+ compared with ERG− cases in the JHU primary tumor cohort; each point represents an individual tumor. B, FASN protein expression by immunostaining is also increased in ERG+ compared with ERG− cases from the PCBN cohort; each point represents an individual tumor. C,FASN probe methylation varies significantly by ERG status for several probes. D,FASN gene methylation mean beta value is not significantly different by ERG status in JHU cohort; each point represents an individual tumor. E,FASN gene expression is significantly higher in ERG fusion positive compared with ERG fusion negative tumors in the WCDT cohort; each point represents an individual tumor. F,FASN gene mean methylation is significantly lower in ERG fusion positive compared with ERG fusion negative tumors in the WCDT cohort; each point represents an individual tumor (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).
Funding
HHS | NIH | National Cancer Institute (NCI)
History
ARTICLE ABSTRACT
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 across multiple racially diverse primary and metastatic prostate cancer cohorts, comparing with FASN protein expression as measured by digitally quantified IHC 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 with 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 with 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.
Here, we leverage multiple independent primary and metastatic prostate cancer cohorts to demonstrate that FASN gene body methylation is highly inversely correlated with FASN gene and protein expression. This finding may shed light on epigenetic mechanisms of FASN regulation in prostate cancer and provides a potentially useful biomarker for selecting patients in future trials of FASN inhibitors.
