title: The prostate cancer TMPRSS2:ERG fusion synergizes with the vitamin D receptor (VDR) to induce CYP24A1 expression-limiting VDR signaling.
abstract: A number of preclinical studies have shown that the activation of the vitamin D receptor (VDR) reduces prostate cancer (PCa) cell and tumor growth. The majority of human PCas express a transmembrane protease serine 2 (TMPRSS2):erythroblast transformation-specific (ETS) fusion gene, but most preclinical studies have been performed in PCa models lacking TMPRSS2:ETS in part due to the limited availability of model systems expressing endogenous TMPRSS2:ETS. The level of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25D), is controlled in part by VDR-dependent induction of cytochrome P450, family 24, subfamily 1, polypeptide1 (CYP24A1), which metabolizes 1,25D to an inactive form. Because ETS factors can cooperate with VDR to induce rat CYP24A1, we tested whether TMPRSS2:ETS would cause aberrant induction of human CYP24A1 limiting the activity of VDR. In TMPRSS2:ETS positive VCaP cells, depletion of TMPRSS2:ETS substantially reduced 1,25D-mediated CYP24A1 induction. Artificial expression of the type VI+72 TMPRSS2:ETS isoform in LNCaP cells synergized with 1,25D to greatly increase CYP24A1 expression. Thus, one of the early effects of TMPRSS2:ETS in prostate cells is likely a reduction in intracellular 1,25D, which may lead to increased proliferation. Next, we tested the net effect of VDR action in TMPRSS2:ETS containing PCa tumors in vivo. Unlike previous animal studies performed on PCa tumors lacking TMPRSS2:ETS, EB1089 (seocalcitol) (a less calcemic analog of 1,25D) did not inhibit the growth of TMPRSS2:ETS containing VCaP tumors in vivo, suggesting that the presence of TMPRSS2:ETS may limit the growth inhibitory actions of VDR. Our findings suggest that patients with TMPRSS2:ETS negative tumors may be more responsive to VDR-mediated growth inhibition and that TMPRSS2:ETS status should be considered in future clinical trials.
authors.affiliation: Departments of Molecular and Cellular Biology (J.-S.K., J.M.R., W.E.B., N.L.W.) and Pathology and Immunology (L.S., J.W., M.M.I.), Baylor College of Medicine, Houston, Texas 77030.
authors.forename: Jung-Sun
authors.initials: JS
authors.lastname: Kim
authors.forename: Justin M
authors.initials: JM
authors.lastname: Roberts
authors.forename: William E
authors.initials: WE
authors.lastname: Bingman
authors.forename: Longjiang
authors.initials: L
authors.lastname: Shao
authors.forename: Jianghua
authors.initials: J
authors.lastname: Wang
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Weigel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D050939:Gene Fusion; D006801:Humans; D008297:Male; D051379:Mice; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D018167:Receptors, Calcitriol / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D015854:Up-Regulation; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C072312:ERG protein, human; D018167:Receptors, Calcitriol; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human