title: The PML isoform IV is a negative regulator of nuclear EGFR's transcriptional activity in lung cancer.
abstract: 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.
authors.affiliation: Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Kuo
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chen
authors.forename: Hsiang-Yi
authors.initials: HY
authors.lastname: Chang
authors.forename: Jen-Chong
authors.initials: JC
authors.lastname: Jeng
authors.forename: Erh-Hsuan
authors.initials: EH
authors.lastname: Lin
authors.forename: Chih-Ming
authors.initials: CM
authors.lastname: Pan
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chang
authors.forename: Mong-Lien
authors.initials: ML
authors.lastname: Wang
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chou
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
mesh_terms: D000107:Acetylation; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D006657:Histones; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C070576:PML protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1