E2F1-induced upregulation of long noncoding RNA LINC00668 predicts a poor prognosis of gastric cancer and promotes cell proliferation through epigenetically silencing of CKIs

// Erbao Zhang 1,* , Dandan Yin 2,* , Liang Han 3,* , Xuezhi He 1 , Xinxin Si 1 , Wenming Chen 4 , Rui Xia 1 , Tongpeng Xu 4 , Dongying Gu 5 , Wei De 1 , Renhua Guo 4 , Zhi Xu 5 and Jinfei Chen 5,6 1 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, PR China 2 Central Laboratory, the Second Affiliated Hospital of Southeast University, Nanjing, Jiangsu, PR China 3 Department of Oncology, Xuzhou Central Hospital, Affiliated Xuzhou Hospital, College of Medicine, Southeast University, Xuzhou, Jiangsu, PR China 4 Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China 5 Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, PR China 6 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, PR China 7 Departments of Pathology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, PR China * These authors have contributed equally to this work and should be regarded as joint first authors Correspondence to: Jinfei Chen, email: // Zhi Xu, email: // Renhua Guo, email: // Wei De, email: // Keywords : E2F1, LINC00668, cell cycle, proliferation, gastric cancer Received : March 10, 2015 Accepted : December 12, 2015 Published : December 23, 2015 Abstract Recently, long noncoding RNAs (lncRNAs) have been shown to have important regulatory roles in human cancer biology. By utilizing publicly available lncRNAs expression profiling data and integrating analyses, we screened out LINC00668, whose expression is significantly increased and correlated with outcomes in gastric cancer (GC). Further experiments revealed that LINC00668 knockdown significantly repressed proliferation, both in vitro and in vivo . Mechanistic investigations showed that LINC00668 was a direct transcriptional target of E2F transcription factor 1 (E2F1). We further demonstrated that LINC00668 was associated with PRC2 and that this association was required for epigenetic repression of cyclin-dependent protein kinase inhibitors (CKIs), including p15, p16, p21, p27 and p57, thus contributing to the regulation of the gastric cancer cell cycle. Our results suggest that E2F1-activated LINC00668, as a cell cycle regulator, enriches the mechanistic link between lncRNA and the E2F1-mediated cell cycle regulation pathway and may serve as a candidate prognostic biomarker and target for new therapies in human gastric cancer.