FASN Gene Methylation is Associated with Fatty Acid Synthase Expression and Clinical-genomic Features of Prostate Cancer.

Autor:	Dairo O; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., DePaula Oliveira L; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Schaffer E; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Vidotto T; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Mendes AA; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Lu J; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland., Huynh SV; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Hicks J; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Sowalsky AG; Laboratory of Genitourinary Cancer Pathogenesis, NCI, Bethesda, Maryland., De Marzo AM; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Joshu CE; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland., Hanratty B; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington., Sfanos KS; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland., Isaacs WB; Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland., Haffner MC; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Center, Seattle, Washington., Lotan TL; Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Urology, Johns Hopkins School of Medicine, Baltimore, Maryland.; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Jan 18; Vol. 4 (1), pp. 152-163.
DOI:	10.1158/2767-9764.CRC-23-0248
Abstrakt:	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. Significance: 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. (© 2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu