Long non-coding RNA SNHG15 inhibits P15 and KLF2 expression to promote pancreatic cancer proliferation through EZH2-mediated H3K27me3

Abstract

// Zhonghua Ma 1, 2, * , Hesuyuan Huang 3, 6, * , Jirong Wang 2, * , Yan Zhou 4, * , Fuxing Pu 5 , Qinghong Zhao 6 , Peng Peng 7 , Bingqing Hui 1, 2 , Hao Ji 1, 2 and Keming Wang 1, 2 1 The Second Clinical Medical College of Nanjing Medical University, Nanjing 210000, Jiangsu, People’s Republic of China 2 Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, People’s Republic of China 3 Department of Cardiothoracic Surgery, Children’s Hospital of Nanjing Medical University, Nanjing 210008, Jiangsu, People’s Republic of China 4 Department of Oncology, The Affiliated Yixing Hospital of Jiangsu University, Wuxi 214200, Jiangsu, People’s Republic of China 5 Department of Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, People’s Republic of China 6 Department of General Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, People’s Republic of China 7 Department of Oncology, Second Hospital of Nanjing, Nanjing 210000, Jiangsu, People's Republic of China * These authors have contributed equally to this work Correspondence to: Keming Wang, email: kemingwang@njmu.edu.cn Keywords: long noncoding RNA, SNHG15, pancreatic cancer, proliferation, P15 and KLF2 Received: March 14, 2017      Accepted: May 29, 2017      Published: August 18, 2017 ABSTRACT Long non-coding RNA (lncRNA) is emerging as an critical regulator in multiple cancers, including pancreatic cancer (PC). Recently, lncRNA SNHG15 was found to be up-regulated in gastric cancer and hepatocellular carcinoma, exerting oncogenic effects. Nevertheless, the biological function and regulatory mechanism of SNHG15 remain unclear in pancreatic cancer (PC). In this study, we reported that SNHG15 expression was also upregulated in PC tissues, and its overexpression was remarkably associated with tumor size, tumor node metastasis (TNM) stage and lymph node metastasis in patients with PC. SNHG15 knockdown inhibited proliferative capacities and suppressed apoptotic rate of PC cells in vitro , and impaired in-vivo tumorigenicity. Additionally, RNA immunoprecipitation (RIP) assays showed that SNHG15 epigenetically repressed the P15 and Kruppel-like factor 2 (KLF2) expression via binding to enhancer of zeste homolog 2 (EZH2), and chromatin immunoprecipitation assays (CHIP) assays demonstrated that EZH2 was capable of binding to promoter regions of P15 and KLF2 to induce histone H3 lysine 27 trimethylation (H3K27me3). Furthermore, rescue experiments indicated that SNHG15 oncogenic function partially involved P15 and KLF2 repression. Consistently, an inverse correlation between the expression of SNHG15 and traget genes were found in PC tissues. Our results reported that SNHG15 could act as an oncogene in PC, revealing its potential value as a biomarker for early detection and individualized therapy.