XIAP RING domain mediates miR-4295 expression and subsequently inhibiting p63α protein translation and promoting transformation of bladder epithelial cells

// Honglei Jin 1, 2 , Jiheng Xu 2 , Xirui Guo 2 , Haishan Huang 1 , Jingxia Li 2 , Minggang Peng 2 , Junlan Zhu 2 , Zhongxian Tian 2 , Xue-Ru Wu 3, 4, 5 , Moon-Shong Tang 2 , Chuanshu Huang 1, 2 1 Zhejiang Provincial Key Laboratory for Technology & Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China 2 Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo, NY 10987, USA 3 Department of Urology, New York University School of Medicine, New York, NY 10016, USA 4 Department of Pathology, New York University School of Medicine, New York, NY 10016, USA 5 VA Medical Center in Manhattan, New York, NY 10010, USA Correspondence to: Chuanshu Huang, email: chuanshu.huang@nyumc.org Keywords: bladder cancer transformation, XIAP, RING domain, p63α Received: March 02, 2016      Accepted: June 13, 2016      Published: July 18, 2016 ABSTRACT The X-linked inhibitor of apoptosis protein (XIAP) contains three N-terminal BIR domains that mediate anti-apoptosis and one C-terminal RING finger domain whose function(s) are not fully defined. Here we show that the RING domain of XIAP strongly inhibits the expression of p63α, a known tumor suppressor. XIAP knockdown in urothelial cells or RING deletion in knockin mice markedly upregulates p63α expression. This RING-mediated p63α downregulation is critical for the malignant transformation of normal urothelial cells following EGF treatment. We further show that the RING domain promotes Sp1-mediated transcription of miR-4295 which targets the 3’UTR of p63α mRNA and consequently inhibits p63α translation. Our results reveal a previously unknown function of the RING of XIAP in promoting miR-4295 transcription, thereby reducing p63α translation and enhancing urothelial transformation. Our data offer novel insights into the multifunctional effects of the XIAP RING domain on urothelial tumorigenesis and the potential for targeting this frequently overexpressed protein as a therapeutic alternative.