title: KLF4 downregulates hTERT expression and telomerase activity to inhibit lung carcinoma growth.
abstract: 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.
authors.affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Wenxian
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yunlu
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Breast Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Kezhen
authors.initials: K
authors.lastname: Lv
authors.affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Yongxia
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Linbo
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Surgical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Luo
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Tianze
authors.initials: T
authors.lastname: Liu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wenlin
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Thoracic Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Sun
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Guangzhou, China.|State Key Laboratory of Targeted Drug for Tumors of Guangdong Province, Guangzhou Double Bioproduct Inc., Guangzhou, China.
authors.forename: Wu-Guo
authors.initials: WG
authors.lastname: Deng
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D019098:Telomerase
keywords: KLF4; MAPK; cancer prognosis; hTERT; lung cancer