title: Dysregulation of cholesterol homeostasis in human prostate cancer through loss of ABCA1.
abstract: Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By conducting next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to transactivation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate- to high-grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 downregulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest that cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression.
authors.affiliation: Glickman Urological & Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Byron H
authors.initials: BH
authors.lastname: Lee
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Taylor
authors.forename: Peggy
authors.initials: P
authors.lastname: Robinet
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Jessica
authors.initials: J
authors.lastname: Schweitzer
authors.forename: Ephraim
authors.initials: E
authors.lastname: Sehayek
authors.forename: Sara M
authors.initials: SM
authors.lastname: Falzarano
authors.forename: Cristina
authors.initials: C
authors.lastname: Magi-Galluzzi
authors.forename: Eric A
authors.initials: EA
authors.lastname: Klein
authors.forename: Angela H
authors.initials: AH
authors.lastname: Ting
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D019175:DNA Methylation; D006706:Homeostasis; D006801:Humans; D008297:Male; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000378:metabolism*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol