Oncotarget

Research Papers:

Dynein axonemal heavy chain 8 promotes androgen receptor activity and associates with prostate cancer progression

Yu Wang _, Russell J. Ledet, Keren Imberg-Kazdan, Susan K. Logan and Michael J. Garabedian

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Oncotarget. 2016; 7:49268-49280. https://doi.org/10.18632/oncotarget.10284

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Abstract

Yu Wang1,2, Russell J. Ledet2,3, Keren Imberg-Kazdan2, Susan K. Logan1,3, Michael J. Garabedian1,3

1Department of Urology, New York University School of Medicine, New York, NY, 10016, USA

2Department of Microbiology, New York University School of Medicine, New York, NY, 10016, USA

3Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA

Correspondence to:

Yu Wang, email: yu.wang@med.nyu.edu

Keywords: prostate cancer, DNAH8, androgen receptor, prognosis, metastasis

Received: February 23, 2016     Accepted: May 28, 2016     Published: June 24, 2016

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.


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