title: Dynein axonemal heavy chain 8 promotes androgen receptor activity and associates with prostate cancer progression.
abstract: To gain insight into cellular factors regulating AR action that could promote castration resistant prostate cancer (CRPC), we performed a genome-wide RNAi screen for factors that promote ligand-independent AR transcriptional activity and integrated clinical databases for candidate genes that are positively associated with prostate cancer metastasis and recurrence. From this analysis, we identified Dynein Axonemal Heavy Chain 8 (DNAH8) as an AR regulator that displayed higher mRNA expression in metastatic than in primary tumors, and showed high expression in patients with poor prognosis. Axonemal dyneins function in cellular motility, but the function of DNAH8 in prostate cancer or other cell types has not been reported. DNAH8 is on chromosome 6q21.2, a cancer-associated amplicon, and is primarily expressed in prostate and testis. Its expression is higher in primary tumors compared to normal prostate, and is further increased in metastatic prostate cancers. Patients expressing high levels of DNAH8 have a greater risk of relapse and a poor prognosis after prostatectomy. Depletion of DNAH8 in prostate cancer cells suppressed AR transcriptional activity and proliferation. Androgen treatment increased DNAH8 mRNA expression, and AR bound the DNAH8 promoter sequence indicating DNAH8 is an AR target gene. Thus, DNAH8 is a new regulator of AR associated with metastatic tumors and poor prognosis.
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.|Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ledet
authors.affiliation: Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Imberg-Kazdan
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Logan
authors.affiliation: Department of Urology, New York University School of Medicine, New York, NY, 10016, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Garabedian
mesh_terms: D056444:Axonemal Dyneins / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: C410798:AR protein, human; D012333:RNA, Messenger; D011944:Receptors, Androgen; D056444:Axonemal Dyneins
keywords: DNAH8; androgen receptor; metastasis; prognosis; prostate cancer