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.

Antiproliferative activity of novel imidazopyridine derivatives on castration-resistant human prostate cancer cells

“…In the present study, LNCaP C-81 cells were used as the primary cell model for our studies because these cells exhibit many properties of CR PCa [12-14,33]. We first demonstrated the antiproliferative efficacy of three novel imidazopyridine derivatives on LNCaP C-81 cells (Fig.…”

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

“…TERE1 expression was found to be greatly reduced in many prostate tumors, often absent as protein in metastatic prostate tumors, and when its expression was induced in prostate carcinoma cell lines, their rate of proliferation was greatly reduced ( 134 ). In a recent study, TERE1 transcript and protein expression was inversely related to cholesterol synthesis in a cell culture model of castration-resistant prostate cancer, using the cell line LnCap-C81 ( 135 ). The mechanism was predominantly through genes regulated by the SXR nuclear hormone receptor which is downregulated in this cell line compared with the parental line from which it was derived ( 135 ).…”

“…In a recent study, TERE1 transcript and protein expression was inversely related to cholesterol synthesis in a cell culture model of castration-resistant prostate cancer, using the cell line LnCap-C81 ( 135 ). The mechanism was predominantly through genes regulated by the SXR nuclear hormone receptor which is downregulated in this cell line compared with the parental line from which it was derived ( 135 ). Groups of genes involved in the hydroxylation and cellular effl ux of cholesterol and in steroid catabolism were all induced by the expression of TERE1 protein or the addition of MK-4 to the cells implying that UBIAD1/ TERE1 links cholesterol metabolism and the castration-resistant prostate cancer phenotype through its product MK-4 ( 135 ).…”

Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during drosophila hematopoiesis

“…It encodes a protein bearing a high sequence identity with human UBIAD1 protein (McGarvey et al, 2001). UBIAD1 gene, firstly identified in SCCD (Schnyder crystalline corneal dystrophy) patients, was found to participate in modulation of the cell cholesterol level (Costa et al, 2009;Fredericks et al, 2011Fredericks et al, , 2013bOrr et al, 2007). In addition, loss of function of UBIAD1 tends to cause the progression of certain types of cancers such as bladder carcinoma and prostate carcinoma (McGarvey et al, 2001(McGarvey et al, , 2005.…”