Abstract 3047: The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer.

Abstract

Abstract EGF 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 (NSCLC) 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 PMIV overexpression. We also found that PMLIV has protein-protein interactions 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. Citation Format: Hong-Yi Kuo, Yi-Chen Chen, Hsiang-Yi Chang, Jen-Chong Jeng, Erh-Hsuan Lin, Chih-Ming Pan, Mong-Lien Wang, Yu-Ting Chou, Hsiu-Ming Shih, Cheng-Wen Wu. The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3047. doi:10.1158/1538-7445.AM2013-3047