title: CYP27A1 Loss Dysregulates Cholesterol Homeostasis in Prostate Cancer.
abstract: In this study, we used a bioinformatic approach to identify genes whose expression is dysregulated in human prostate cancers. One of the most dramatically downregulated genes identified encodes CYP27A1, an enzyme involved in regulating cellular cholesterol homeostasis. Importantly, lower CYP27A1 transcript levels were associated with shorter disease-free survival and higher tumor grade. Loss of CYP27A1 in prostate cancer was confirmed at the protein level by immunostaining for CYP27A1 in annotated tissue microarrays. Restoration of CYP27A1 expression in cells where its gene was silenced attenuated their growthin vitroand in tumor xenografts. Studies performedin vitrorevealed that treatment of prostate cancer cells with 27-hydroxycholesterol (27HC), an enzymatic product of CYP27A1, reduced cellular cholesterol content in prostate cancer cell lines by inhibiting the activation of sterol regulatory-element binding protein 2 and downregulating low-density lipoprotein receptor expression. Our findings suggest that CYP27A1 is a critical cellular cholesterol sensor in prostate cells and that dysregulation of the CYP27A1/27HC axis contributes significantly to prostate cancer pathogenesis.Cancer Res; 77(7); 1662-73. ©2017 AACR.
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina.|Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Alfaqih
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.|Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign; and University of Illinois Cancer Center, Chicago, Illinois.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Jeffery S
authors.initials: JS
authors.lastname: Jasper
authors.affiliation: Department of Surgery, Duke University, Durham, North Carolina.|Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Everardo
authors.initials: E
authors.lastname: Macias
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Joseph
authors.initials: J
authors.lastname: Geradts
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.|Department of Proteomics and Metabolomics Shared Resource, Duke University, Durham, North Carolina.
authors.forename: J Will
authors.initials: JW
authors.lastname: Thompson
authors.affiliation: Department of Proteomics and Metabolomics Shared Resource, Duke University, Durham, North Carolina.
authors.forename: Laura G
authors.initials: LG
authors.lastname: Dubois
authors.affiliation: Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Freeman
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina.
authors.forename: Jen-Tsan
authors.initials: JT
authors.lastname: Chi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina. Donald.mcdonnell@duke.edu stephen.freedland@cshs.org.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Department of Surgery and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California. Donald.mcdonnell@duke.edu stephen.freedland@cshs.org.|Surgery Section, Durham VA Medical Center, Durham, North Carolina.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Freedland
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics*; D002784:Cholesterol / Q000378:metabolism*; D019295:Computational Biology; D015971:Gene Expression Regulation, Enzymologic; D006706:Homeostasis; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors
chemical_list: D006888:Hydroxycholesterols; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C076996:27-hydroxycholesterol; D002784:Cholesterol; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase