Oncotarget

Research Papers:

Regulation of androgen receptor splice variant AR3 by PCGEM1

Ziqiang Zhang _, Nanjiang Zhou, Jianguo Huang, Tsui-Ting Ho, Zhuxian Zhu, Zhongmin Qiu, Xinchun Zhou, Chunxue Bai, Fangting Wu, Min Xu and Yin-Yuan Mo

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Oncotarget. 2016; 7:15481-15491. https://doi.org/10.18632/oncotarget.7139

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Abstract

Ziqiang Zhang1,2, Nanjiang Zhou3, Jianguo Huang3, Tsui-Ting Ho1, Zhuxian Zhu4, Zhongmin Qiu2, Xinchun Zhou5, Chunxue Bai6, Fangting Wu7, Min Xu8, Yin-Yuan Mo1

1Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

2Department of Pulmonary Medicine, Tongji Hospital, Tongji University, Shanghai, China

3Department of Biochemistry and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA

4Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China

5Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA

6Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, PR China

7System Biosciences, Mountain View, CA, USA

8Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China

Correspondence to:

Yin-Yuan Mo, e-mail: ymo@umc.edu

Keywords: PCGEM1, androgen receptor, AR3, castration resistance, lncRNA

Received: October 06, 2015     Accepted: January 23, 2016     Published: February 02, 2016

ABSTRACT

The androgen receptor (AR) is required for prostate development and is also a major driver of prostate cancer pathogenesis. Thus androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. However, castration resistance due to expression of constitutively active AR splice variants is a significant challenge to prostate cancer therapy; little is known why effectiveness of ADT can only last for a relatively short time. In the present study, we show that PCGEM1 interacts with splicing factors heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and U2AF65, as determined by RNA precipitation and Western blot, suggesting a role for PCGEM1 in alternative splicing. In support of this possibility, PCGEM1 is correlated with AR3, a predominant and clinically important form of AR splice variants in prostate cancer. Moreover, androgen deprivation (AD) induces PCGEM1 and causes its accumulation in nuclear speckles. Finally, we show that the AD-induced PCGEM1 regulates the competition between hnRNP A1 and U2AF65 for AR pre-mRNA. AD promotes PCGEM1 to interact with both hnRNP A1 and U2AF65 with different consequences. While the interaction of PCGEM1 with hnRNP A1 suppresses AR3 by exon skipping, its interaction with U2AF65 promotes AR3 by exonization. Together, we demonstrate an AD-mediated AR3 expression involving PCGEM1 and splicing factors.


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