title: The response of the prostate to circulating cholesterol: activating transcription factor 3 (ATF3) as a prominent node in a cholesterol-sensing network.
abstract: Elevated circulating cholesterol is a systemic risk factor for cardiovascular disease and metabolic syndrome, however the manner in which the normal prostate responds to variations in cholesterol levels is poorly understood. In this study we addressed the molecular and cellular effects of elevated and suppressed levels of circulating cholesterol on the normal prostate. Integrated bioinformatic analysis was performed using DNA microarray data from two experimental formats: (1) ventral prostate from male mice with chronically elevated circulating cholesterol and (2) human prostate cells exposed acutely to cholesterol depletion. A cholesterol-sensitive gene expression network was constructed from these data and the transcription factor ATF3 was identified as a prominent node in the network. Validation experiments confirmed that elevated cholesterol reduced ATF3 expression and enhanced proliferation of prostate cells, while cholesterol depletion increased ATF3 levels and inhibited proliferation. Cholesterol reduction in vivo alleviated dense lymphomononuclear infiltrates in the periprostatic adipose tissue, which were closely associated with nerve tracts and blood vessels. These findings open new perspectives on the role of cholesterol in prostate health, and provide a novel role for ATF3, and associated proteins within a large signaling network, as a cholesterol-sensing mechanism.
authors: Division of Cancer Biology and Therapeutics, Departments of Surgery and Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA. Jayoung.Kim@cshs.org
authors: Jayoung
authors: J
authors: Kim
authors: Dolores
authors: D
authors: Di Vizio
authors: Taek-Kyun
authors: TK
authors: Kim
authors: Jonghwan
authors: J
authors: Kim
authors: Minjung
authors: M
authors: Kim
authors: Kristine
authors: K
authors: Pelton
authors: Steven K
authors: SK
authors: Clinton
authors: Tsonwin
authors: T
authors: Hai
authors: Daehee
authors: D
authors: Hwang
authors: Keith R
authors: KR
authors: Solomon
authors: Michael R
authors: MR
authors: Freeman
mesh_terms: D051700:Activating Transcription Factor 3 / Q000096:biosynthesis*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002784:Cholesterol / Q000097:blood*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011467:Prostate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D002784:Cholesterol