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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 is upregulated and FASN gene is hypomethylated in tumor compared with benign tissue in JHU primary tumor cohort. A, Dual FASN and p63 IHC assay in representative primary prostate tumor from JHU cohort (scale bar = 250 µm). FASN and p63 are both labeled in brown. Benign glands with nuclear p63 labeling in basal cells (arrow) are then manually excluded from analysis and FASN scoring is performed on tumor glands only. See Supplementary Fig. S2. B, Quantified FASN protein expression by immunostaining in benign prostate glands versus tumor glands from JHU cohort; each point represents the mean H-score from a single prostatectomy sample, analyzed in a matched analysis. C, Representative plots of beta values (range: 0–1) by FASN probe on InfiniumEPIC for a representative paired benign (blue) and tumor (red) sample set from the JHU cohort. TSS: transcription start site; UTR: untranslated region. D,FASN gene methylation beta values by FASN probe for benign tissue versus tumor tissue in JHU cohort. E, Mean FASN gene methylation probe beta values for benign tissue versus tumor tissue in JHU cohort. Each point represents the mean beta value from a single prostatectomy sample analyzed in a matched analysis (*, 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.
