Long noncoding RNA ZFAS1 promotes gastric cancer cells proliferation by epigenetically repressing KLF2 and NKD2 expression

Abstract

// Fengqi Nie 1, * , Xiang Yu 2, * , Mingde Huang 3, * , Yunfei Wang 4 , Min Xie 5 , Hongwei Ma 6 , Zhaoxia Wang 1 , Wei De 5 and Ming Sun 4 1 Department of Oncology, Second Affiliated Hospital, Nanjing Medical University, Nanjing, People’s Republic of China 2 Department of General Surgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University Medical College, Yantai, People’s Republic of China 3 Department of Medical Oncology, Huai’an First People’s Hospital, Nanjing Medical University, Huai’an, People’s Republic of China 4 Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX, USA 5 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, People’s Republic of China 6 Department of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China * These authors contributed equally to this work and should be regarded as joint first authors Correspondence to: Ming Sun, email: msun7@mdanderson.org Zhaoxia Wang, email: zhaoxiawang88@hotmail.com Wei De, email: dewei@njmu.edu.cn Keywords: long noncoding RNA, ZFAS1, gastric cancer, proliferation, KLF2 and NKD2 Received: February 10, 2016     Accepted: May 02, 2016     Published: May 26, 2016 ABSTRACT Recently, long noncoding RNAs have been emerged as critical regulators of human disease and prognostic markers in several cancers, including gastric cancer. In this study, we globally assessed the transcriptomic differences of lncRNAs in gastric cancer using publicly available microarray data from Gene Expression Omnibus (GEO) and identified an oncogenetic lncRNA ZFAS1, which may promote gastric tumorigenesis. ZFAS1 has been found to be upregulated and function as oncogene in colorectal cancer and hepatocellular carcinoma, but its expression pattern, biological function and underlying mechanism in gastric cancer is still undetermined. Here, we reported that ZFAS1 expression is also overexpressed in gastric cancer, and its increased level is associated with poor prognosis and shorter survival. Knockdown of ZFAS1 impaired gastric cancer cells proliferation and induced apoptosis in vitro, and inhibited tumorigenicity of gastric cancer cells in vivo. Mechanistically, RNA immunoprecipitation and RNA pull-down experiment showed that ZFAS1 could simultaneously interact with EZH2 and LSD1/CoREST to repress underlying targets KLF2 and NKD2 transcription. In addition, rescue experiments determined that ZFAS1 oncogenic function is partly dependent on repressing KLF2 and NKD2. Taken together, our findings illuminate how ZFAS1 over-expression confers an oncogenic function in gastric cancer.