The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer

Hong Yi Kuo, Yi Chen Chen, Hsiang Yi Chang, Jen Chong Jeng, Erh Hsuan Lin, Chih Ming Pan, Yu Wei Chang, Mong Lien Wang, Yu Ting Chou, Hsiu Ming Shih, Cheng-Wen Wu Lee*

*此作品的通信作者

研究成果: Article同行評審

13 引文 斯高帕斯(Scopus)

摘要

Epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase, which can transduce intracellular signals responsible for cell proliferation. It is frequently overexpressed and/or constitutively activated in non-small cell lung cancer and thus is considered as a major cause of this disease. Recently, EGFR has been found in the nucleus where the nuclear EGFR (nEGFR) can function as a transcription factor activating the transcription of genes such as cyclin D1 gene (CCND1), which is essential for cell proliferation. Nevertheless, how nEGFR's transcriptional activity is regulated remains unclear. Promyelocytic leukemia protein (PML) is a tumor suppressor, which is lost in various cancers including lung cancer. However, the role of PML in the suppression of lung cancer growth is still unclear. When we investigated the role of PML in the regulation of lung cancer cell growth, we found that PML isoform IV (PMLIV) preferentially represses the growth of lung cancer cells bearing constitutively active EGFR. Besides, when growing in the EGFR activating conditions, the growth of EGFR wild-type bearing A549 cells has been repressed by PMLIV overexpression. We also found that PMLIV can interact physically with nEGFR and represses the transcription of nEGFR target genes. We showed that PMLIV is recruited by nEGFR to the target promoters and reduces the promoter histone acetylation level via HDAC1. Together, our results suggest that PMLIV interacts with nEGFR upon EGFR activation and represses the transcription of nEGFR target genes such as CCND1 and thus leading to inhibition of the lung cancer cell growth.

原文English
頁(從 - 到)1708-1716
頁數9
期刊Carcinogenesis
34
發行號8
DOIs
出版狀態Published - 1 八月 2013

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