title: Regulation of androgen receptor splice variant AR3 by PCGEM1.
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.
authors: Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Pulmonary Medicine, Tongji Hospital, Tongji University, Shanghai, China.
authors: Ziqiang
authors: Z
authors: Zhang
authors: Department of Biochemistry and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Nanjiang
authors: N
authors: Zhou
authors: Department of Biochemistry and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Jianguo
authors: J
authors: Huang
authors: Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Tsui-Ting
authors: TT
authors: Ho
authors: Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China.
authors: Zhuxian
authors: Z
authors: Zhu
authors: Department of Pulmonary Medicine, Tongji Hospital, Tongji University, Shanghai, China.
authors: Zhongmin
authors: Z
authors: Qiu
authors: Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Xinchun
authors: X
authors: Zhou
authors: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors: Chunxue
authors: C
authors: Bai
authors: System Biosciences, Mountain View, CA, USA.
authors: Fangting
authors: F
authors: Wu
authors: Department of Gastroenterology, Affiliated Hospital of Jiangsu University, Zhenjiang, Jiangsu, China.
authors: Min
authors: M
authors: Xu
authors: Department of Pharmacology/Toxicology and Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors: Yin-Yuan
authors: YY
authors: Mo
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D062085:RNA, Long Noncoding / Q000378:metabolism*; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; C416084:PCGEM1 non-coding RNA, human; D020033:Protein Isoforms; D062085:RNA, Long Noncoding; D011944:Receptors, Androgen
keywords: AR3; PCGEM1; androgen receptor; castration resistance; lncRNA