title: Lgr4 promotes prostate tumorigenesis through the Jmjd2a/AR signaling pathway.
abstract: Lgr4 (leucine-rich repeat domain containing G protein-coupled receptor 4) is implicated in the transcriptional regulation of multiple histone demethylases in the progression of diverse cancers, but there are few reports concerning the molecular mechanism by which Lgr4 regulates histone demethylase activation in prostate cancer (PCa) progression. As Jmjd2a is a histone demethylase, in the current study, we investigated the relationship between interaction Lgr4 with Jmjd 2a and Jmjd2a/androgen receptor (AR) signaling pathway in PCa progression. Firstly, Lgr4 was overexpressed by transfecting pcDNA3.1(+)/Lgr4 plasmids into PCa (LNCaP and PC-3) cell lines. Next, we found that Lgr4 overexpression promoted Jmjd2a mRNA expression, reduced cell apoptosis and arrested cell cycle in the S phase, these effects were reversed by Jmjd2a silencing. Moreover, Lgr4 overexpression markedly elevated AR levels and its interaction with Jmjd2a, which was tested by co-immunoprecipitation and luciferase reporter assays. Furthermore, interaction AR with PSA promoter (containing an AR response element) was obviously improved by Lgr4 overexpression, and PSA silencing reduced Lgr4-induced cell apoptosis and cell cycle arrest in PCa cells. Taken together, Lgr4 may be a novel tumor marker providing new mechanistic insights into PCa progression. Lgr4 activates Jmjd2a/AR signaling pathway to promote interaction AR with PSA promoter, causing reduction of PCa apoptosis and cell cycle arrest.
authors.affiliation: Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China. Electronic address: jianweizhangjwz@163.com.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Shaojin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Quanquan
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Urology Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
authors.forename: Tianen
authors.initials: T
authors.lastname: Wang
mesh_terms: D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism*; D008297:Male; D011401:Promoter Regions, Genetic / Q000235:genetics; D011467:Prostate / Q000378:metabolism / Q000473:pathology*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics
chemical_list: C410798:AR protein, human; C411562:LGR4 protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D043562:Receptors, G-Protein-Coupled; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human; D017430:Prostate-Specific Antigen
keywords: Jmjd2a/AR; Lgr4; Prostate cancer; Prostate-specific antigen (PSA)