Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer

// Xin-Xing Zhu 1, 2, * , Ya-Wei Yan 1, 2, * , Chun-Zhi Ai 1 , Shan Jiang 1 , Shan-Shan Xu 1 , Min Niu 3 , Xiang-Zhen Wang 4 , Gen-Shen Zhong 5 , Xi-Feng Lu 6 , Yu Xue 7 , Shaoqi Tian 8 , Guangyao Li 9 , Shaojun Tang 10 , Yi-Zhou Jiang 1 1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China 2 Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China 3 Department of Statics, University of Wisconsin-Madison, Madison, WI, USA 4 Maternal and Child Health Hospital of Nanshan District, Shenzhen, Guangdong, China 5 The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China 6 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University, Shenzhen, Guangdong, China 7 Minnan Normal University, Zhangzhou, Fujian, China 8 The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China 9 Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA 10 Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA * These authors contributed equally to this work Correspondence to: Yi-Zhou Jiang, email: jiangyz@szu.edu.cn Keywords: Jarid2, bladder tumors, tumor-initiating cells, p16, histone modification Received: November 24, 2016      Accepted: February 07, 2017      Published: February 20, 2017 ABSTRACT Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo . Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.