title: PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation of MMP2.
abstract: Promyelocytic leukemia protein (PML) is emerging as an important tumor suppressor. Its expression is lost during the progression of several types of cancer, including lung cancer. The EGF receptor (EGFR), a membrane-bound receptor tyrosine kinase, transduces intracellular signals responsible for cell proliferation, differentiation and migration. EGFR activity is frequently abnormally upregulated in lung adenocarcinoma (LAC) and thus is considered to be a driving oncogene for LAC. EGFR translocates into the nucleus and transcriptionally activates genes, such as CCND1, that promote cell growth. Recently, we demonstrated that PML interacted with nuclear EGFR (nEGFR) and suppressed the nEGFR-mediated transcriptional activation of CCND1 in lung cancer cells, thereby restraining cell growth. When we further investigated the interplay between PML and EGFR in lung cancer metastasis, we found that the matrix metalloprotease-2 gene (MMP2) was a novel nEGFR target gene and was repressed by PML. We provide evidence that nEGFR bound to the AT-rich sequence (ATRS) in the MMP2 promoter and enhanced its transcriptional activity. In addition, we demonstrated that PML repressed nEGFR-induced MMP2 transcription and reduced cell invasion. PML was recruited by nEGFR to the MMP2 promoter where it reduced histone acetylation, leading to the transcriptional repression of MMP2. Finally, we demonstrated that PML upregulation by interferon-β (IFNβ) in lung cancer cells decreased MMP2 expression and cell invasion. Together, our results suggested that IFNβ induced PML to inhibit lung cancer metastasis by repressing the nEGFR-mediated transcriptional activation of MMP2.
authors.affiliation: a Institute of Biochemistry and Molecular Biology ; National Yang Ming University ; Taipei , Taiwan.
authors.forename: Hong-Yi
authors.initials: HY
authors.lastname: Kuo
authors.forename: Yen-Sung
authors.initials: YS
authors.lastname: Huang
authors.forename: Chin-Hsiu
authors.initials: CH
authors.lastname: Tseng
authors.forename: Yi-Chen
authors.initials: YC
authors.lastname: Chen
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Chang
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D006657:Histones; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; C070576:PML protein, human; D004815:Epidermal Growth Factor; D016899:Interferon-beta; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2
keywords: ATRS; ATRS, AT-rich sequence; EGFR, EGF receptor; IFNβ, interferon-β; INM, inner nuclear membrane; Interferon-β; LAC, lung adenocarcinoma; MMP2; MMP2, matrix metalloprotease-2; PML; PML, promyelocytic leukemia protein; STAT3; lung adenocarcinoma; nEGFR, nuclear EGFR; nuclear EGFR