Overexpression of USP39 predicts poor prognosis and promotes tumorigenesis of prostate cancer via promoting EGFR mRNA maturation and transcription elongation

Abstract

// Yi Huang 1, 2, * , Xiu-Wu Pan 1, 3, * , Lin Li 1 , Lu Chen 1 , Xi Liu 1 , Jian-Lei Lu 4 , Xiao-Mei Zhu 4 , Hai Huang 1 , Qi-Wei Yang 1 , Jian-Qing Ye 3 , Si-Shun Gan 3 , Lin-Hui Wang 1 , Yi Hong 4 , Dan-Feng Xu 5 , Xin-Gang Cui 3 1 Department of Urinary Surgery of Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China 2 The 2nd Department of Oncology of Chenggong Hospital, Xiamen University, Xiamen, 361003, China 3 Department of Urinary Surgery of Third Affiliated Hospital, Second Military Medical University, Shanghai, 201805, China 4 R & D Departmemt of DuruoBiotechnologies Inc., Shanghai, 200233, China 5 Department of Urinary Surgery of Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China * These authors have contributed equally to this work Correspondence to: Xin-Gang Cui, e-mail: xingangcui@126.com Dan-Feng Xu, e-mail: xu-danfeng@hotmail.com Yi Hong, e-mail: zandh@163.com Keywords: USP39, prostate cancer, prognosis, tumorigenesis, EGFR Received: January 15, 2016     Accepted: February 23, 2016     Published: March 03, 2016 ABSTRACT Castration resistance is a serious problem facing clinical treatment of prostate cancer (PCa). The underlying molecular mechanisms of acquired proliferation ability of tumor cells upon androgen deprivation are largely undetermined. In the present study, we identified that ubiquitin specific peptidase 39 (USP39) was significantly upregulated in PCa samples and cell lines. Elevated USP39 expression was positively correlated with Gleason score, predicted a poor outcome, and functioned as an independent risk factor for biochemical recurrence (BCR) especially in patients with a Gleason score ≤7. Our cell-based study showed that the expression level of USP39 was the highest in AR-negative PCa cell lines. Knockdown of USP39 in PCa cells inhibited cancer colony formation and tumor cell growth, and induced G2/M arrest and cell apoptosis. Microarray analysis suggested that knockdown of USP39 caused a reduced expression of EGFR. Silencing of USP39 inhibited the expression of EGFR 3′-end, and presented a remarkable block to the maturation of EGFR mRNA, suggesting that silencing of USP39 decreased the transcriptional elongation and maturation of EGFR mRNA. Oncomine datasets analysis showed that USP39 expression was positively correlated with EGFR level. The above findings suggest that USP39 plays a vital oncogenic role in the tumorigenesis of PCa and may prove to be a potential biomarker for predicting the prognosis of PCa patients.