Notch3 overexpression enhances progression and chemoresistance of urothelial carcinoma

// Heng Zhang 1, 2 , Limei Liu 1 , Chungang Liu 1 , Jinhong Pan 2 , Gensheng Lu 2 , Zhansong Zhou 2 , Zhiwen Chen 2 , Cheng Qian 1 1 Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China 2 Department of Urology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China Correspondence to: Cheng Qian, email: cqian3184@163.com Zhiwen Chen, email: zhiwen@tmmu.edu.cn Keywords: Notch3, urothelial cancer, cisplatin, histone deacetylase, chemoresistance Received: March 14, 2016      Accepted: December 12, 2016      Published: March 13, 2017 ABSTRACT Abnormal activation of Notch signaling is involved in the etiology of various diseases, including cancer, but the association between Notch3 expression in urothelial cancer and clinical outcome remains unclear, and the molecular mechanisms underlying Notch3 signaling activation are not well defined. In this study we examined 59 urothelial cancer patients and found that Notch3 was more highly expressed in human urothelial cancer tissues than in non-tumorous bladder tissue samples, with Notch3 overexpression being associated with poor clinical outcome. Notch3 knockdown resulted in decreased proliferation of urothelial cancer cells in vitro and decreased xenograft tumor growth in vivo . In addition, Notch3 knockdown rendered urothelial cancer cells more sensitive to cisplatin. Furthermore, suberoylanilide hydroxamic acid (SAHA, a histone deacetylase [HDAC] inhibitor) induced acetylation of NOTCH3, downregulated Notch 3 , prevented urothelial cancer cell proliferation, and induced cell cycle arrest. Taken together, these data suggested that Notch 3 overexpression promotes growth and chemoresistance in urothelial cancer.