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.
Highlights
Despite advances in early diagnosis and combined therapy, lung cancer remains a major public health problem worldwide
Krüppel-like factor 4 (KLF4) was correlated with hTERT expression in lung cancer, and their expression was associated with patient survival
These findings indicated that there might be crosstalk between hTERT and KLF4 in lung carcinoma
Summary
Despite advances in early diagnosis and combined therapy, lung cancer remains a major public health problem worldwide. General therapy for lung cancer consists of surgical tumor resection, multimodal chemotherapy, radiation therapy, or a combination of these regimens. The lung cancer prognosis remains poor, and more effective therapies are urgently needed. The aggressive nature of lung cancer is associated with various molecular abnormalities, including the loss of tumor suppressor genes, activation of oncogenes and somatic mutations of growth factor receptors [2]. A better understanding and improved identification of novel factors involved in lung cancer development and progression are www.impactjournals.com/oncotarget essential for defining tumor classification, improving diagnostic accuracy, predicting patient outcomes and providing more effective treatment strategies
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