title: Crosstalk between nuclear MET and SOX9/β-catenin correlates with castration-resistant prostate cancer.
abstract: Castration-resistant prostate cancer (PCa) (CRPC) is relapse after various forms of androgen ablation therapy and causes a major mortality in PCa patients, yet the mechanism remains poorly understood. Here, we report the nuclear form of mesenchymal epithelial transition factor (nMET) is essential for CRPC. Specifically, nMET is remarkably increased in human CRPC samples compared with naïve samples. Androgen deprivation induces endogenous nMET and promotes cell proliferation and stem-like cell self-renewal in androgen-nonresponsive PCa cells. Mechanistically, nMET activates SRY (sex determining region Y)-box9, β-catenin, and Nanog homeobox and promotes sphere formation in the absence of androgen stimulus. Combined treatment of MET and β-catenin enhances the inhibition of PCa cell growth. Importantly, MET accumulation is detected in nucleus of recurrent prostate tumors of castrated Pten/Trp53 null mice, whereas MET elevation is predominantly found in membrane of naïve tumors. Our findings reveal for the first time an essential role of nMET association with SOX9/β-catenin in CRPC in vitro and in vivo, highlighting that nuclear RTK activate cell reprogramming to drive recurrence, and targeting nMET would be a new avenue to treat recurrent cancers.
authors.affiliation: Department of Biochemistry and Cancer Biology (Y.X., W.L., S.L., Q.Y., Z.C.), Meharry Medical College, Nashville, Tennessee 37208; Department of Surgery and Division of Urology (B.S.C.), Memorial Sloan-Kettering Cancer Center, New York, New York 10065; and Vancouver Prostate Centre and Department of Urologic Sciences (E.L., Y.W., L.F., M.G.), The University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
authors.forename: Yingqiu
authors.initials: Y
authors.lastname: Xie
authors.forename: Wenfu
authors.initials: W
authors.lastname: Lu
authors.forename: Shenji
authors.initials: S
authors.lastname: Liu
authors.forename: Qing
authors.initials: Q
authors.lastname: Yang
authors.forename: Brett S
authors.initials: BS
authors.lastname: Carver
authors.forename: Estelle
authors.initials: E
authors.lastname: Li
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.forename: Zhenbang
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D011467:Prostate / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism* / Q000473:pathology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D046888:Tissue Array Analysis; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D011944:Receptors, Androgen; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D051176:beta Catenin; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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