KLF4 downregulates hTERT expression and telomerase activity to inhibit lung carcinoma growth
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Wenxian Hu1,*, Yunlu Jia1,*, Xiangsheng Xiao2, Kezhen Lv3, Yongxia Chen1, Linbo Wang1, Xiao Luo1, Tianze Liu2, Wenbin Li2, Yixin Li2, Changlin Zhang2, Zhenglong Yu4, Wenlin Huang2,5, Bing Sun4, Wu-guo Deng2,5
1Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
2Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China
3Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
4Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
5State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China
*These authors contributed equally to this work
Wenxian Hu, email: email@example.com
Bing Sun, email: firstname.lastname@example.org
Wu-guo Deng, email: email@example.com
Keywords: KLF4, hTERT, MAPK, lung cancer, cancer prognosis
Received: January 07, 2016 Accepted: April 16, 2016 Published: May 02, 2016
Krüppel-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.
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