KLF4 downregulates hTERT expression and telomerase activity to inhibit lung carcinoma growth.
KLF4 downregulates hTERT expression and telomerase activity to inhibit lung carcinoma growth.
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KLF4下调hTERT表达和端粒酶活性抑制肺癌生长
DOI：
10.18632/oncotarget.9141
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发表时间：
2016-08-16
期刊：
影响因子：
--
通讯作者：
Deng WG
中科院分区：
文献类型：
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作者：
Hu W;Jia Y;Xiao X;Lv K;Chen Y;Wang L;Luo X;Liu T;Li W;Li Y;Zhang C;Yu Z;Huang W;Sun B;Deng WG
Krüppel样因子4（KLF 4）是一种转录因子，有助于不同的细胞过程，并在各种癌症中充当肿瘤抑制因子或癌基因。以前，我们已经报道了KLF4在肺癌中的肿瘤抑制功能;然而，其精确的调节机制仍然是难以捉摸的。在本研究中，我们发现KLF4在肺癌细胞系和小鼠模型中负调控hTERT表达和端粒酶活性。此外，KLF4和hTERT的表达水平与肺癌患者的临床病理特征显著相关。启动子报告基因分析显示，Ad-KLF4感染的细胞中hTERT启动子活性降低，染色质免疫沉淀分析表明内源性KLF4直接与hTERT启动子区结合。此外，MAPK信号通路被揭示参与KLF4/hTERT调节通路。在小鼠模型中，KLF4的强制表达显著减弱了肺细胞增殖和癌症形成。此外，hTERT过表达可以部分挽救KLF4介导的肺癌细胞抑制作用。综上所述，这些结果表明KLF4通过抑制hTERT和MAPK信号传导抑制肺癌生长。此外，KLF4/hTERT/MAPK通路是一个潜在的肺癌治疗新靶点。
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.