title: The tumor suppressor TERE1 (UBIAD1) prenyltransferase regulates the elevated cholesterol phenotype in castration resistant prostate cancer by controlling a program of ligand dependent SXR target genes.
abstract: Castrate-Resistant Prostate Cancer (CRPC) is characterized by persistent androgen receptor-driven tumor growth in the apparent absence of systemic androgens. Current evidence suggests that CRPC cells can produce their own androgens from endogenous sterol precursors that act in an intracrine manner to stimulate tumor growth. The mechanisms by which CRPC cells become steroidogenic during tumor progression are not well defined. Herein we describe a novel link between the elevated cholesterol phenotype of CRPC and the TERE1 tumor suppressor protein, a prenyltransferase that synthesizes vitamin K-2, which is a potent endogenous ligand for the SXR nuclear hormone receptor. We show that 50% of primary and metastatic prostate cancer specimens exhibit a loss of TERE1 expression and we establish a correlation between TERE1 expression and cholesterol in the LnCaP-C81 steroidogenic cell model of the CRPC. LnCaP-C81 cells also lack TERE1 protein, and show elevated cholesterol synthetic rates, higher steady state levels of cholesterol, and increased expression of enzymes in the de novo cholesterol biosynthetic pathways than the non-steroidogenic prostate cancer cells. C81 cells also show decreased expression of the SXR nuclear hormone receptor and a panel of directly regulated SXR target genes that govern cholesterol efflux and steroid catabolism. Thus, a combination of increased synthesis, along with decreased efflux and catabolism likely underlies the CRPC phenotype: SXR might coordinately regulate this phenotype. Moreover, TERE1 controls synthesis of vitamin K-2, which is a potent endogenous ligand for SXR activation, strongly suggesting a link between TERE1 levels, K-2 synthesis and SXR target gene regulation. We demonstrate that following ectopic TERE1 expression or induction of endogenous TERE1, the elevated cholesterol levels in C81 cells are reduced. Moreover, reconstitution of TERE1 expression in C81 cells reactivates SXR and switches on a suite of SXR target genes that coordinately promote both cholesterol efflux and androgen catabolism. Thus, loss of TERE1 during tumor progression reduces K-2 levels resulting in reduced transcription of SXR target genes. We propose that TERE1 controls the CPRC phenotype by regulating the endogenous levels of Vitamin K-2 and hence the transcriptional control of a suite of steroidogenic genes via the SXR receptor. These data implicate the TERE1 protein as a previously unrecognized link affecting cholesterol and androgen accumulation that could govern acquisition of the CRPC phenotype.
authors.affiliation: Department of Surgery, Division of Urology, University of Pennsylvania and Veterans Affairs Medical Center Philadelphia, Philadelphia, PA, USA. wjfredericks@verizon.net
authors.forename: William J
authors.initials: WJ
authors.lastname: Fredericks
authors.forename: Jorge
authors.initials: J
authors.lastname: Sepulveda
authors.forename: Priti
authors.initials: P
authors.lastname: Lai
authors.forename: John E
authors.initials: JE
authors.lastname: Tomaszewski
authors.forename: Ming-Fong
authors.initials: MF
authors.lastname: Lin
authors.forename: Terry
authors.initials: T
authors.lastname: McGarvey
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.forename: S Bruce
authors.initials: SB
authors.lastname: Malkowicz
mesh_terms: D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D004122:Dimethylallyltranstransferase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D008297:Male; D010641:Phenotype; D000077297:Pregnane X Receptor; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D014812:Vitamin K / Q000494:pharmacology
chemical_list: D008024:Ligands; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D014812:Vitamin K; D002784:Cholesterol; D004122:Dimethylallyltranstransferase; C425464:UBIAD1 protein, human
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