KLF4 downregulates hTERT expression and telomerase activity to inhibit lung carcinoma growth

// Wenxian Hu 1, * , Yunlu Jia 1, * , Xiangsheng Xiao 2 , Kezhen Lv 3 , Yongxia Chen 1 , Linbo Wang 1 , Xiao Luo 1 , Tianze Liu 2 , Wenbin Li 2 , Yixin Li 2 , Changlin Zhang 2 , Zhenglong Yu 4 , Wenlin Huang 2, 5 , Bing Sun 4 , Wu-guo Deng 2, 5 1 Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China 3 Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China 4 Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China 5 State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China * These authors contributed equally to this work Correspondence to: Wenxian Hu, email: 13967169904@163.com Bing Sun, email: dysunbing@163.com Wu-guo Deng, email: dengwg@sysucc.org.cn Keywords: KLF4, hTERT, MAPK, lung cancer, cancer prognosis Received: January 07, 2016      Accepted: April 16, 2016      Published: May 02, 2016 ABSTRACT Kruppel-like factor 4 (KLF4) is a transcription factor that contributes to diverse cellular processes and serves as a tumor suppressor or oncogene in various cancers. Previously, we have reported on the tumor suppressive function of KLF4 in lung cancer; however, its precise regulatory mechanism remains elusive. In this study, we found that KLF4 negatively regulated hTERT expression and telomerase activity in lung cancer cell lines and a mouse model. In addition, the KLF4 and hTERT expression levels were significantly related to the clinicopathological features of lung cancer patients. Promoter reporter analyses revealed the decreased hTERT promoter activity in cells infected with Ad-KLF4, and chromatin immunoprecipitation analysis demonstrated that endogenous KLF4 directly bound to the promoter region of hTERT. Furthermore, the MAPK signaling pathway was revealed to be involved in the KLF4/hTERT modulation pathway. Forced expression of KLF4 profoundly attenuated lung cell proliferation and cancer formation in a murine model. Moreover, hTERT overexpression can partially rescue the KLF4-mediated suppressive effect in lung cancer cells. Taken together, these results demonstrate that KLF4 suppresses lung cancer growth by inhibiting hTERT and MAPK signaling. Additionally, the KLF4/hTERT/MAPK pathway is a potential new therapeutic target for human lung cancer.