title: MicroRNA-7 Compromises p53 Protein-dependent Apoptosis by Controlling the Expression of the Chromatin Remodeling Factor SMARCD1.
abstract: We previously demonstrated that the epidermal growth factor receptor (EGFR) up-regulated miR-7 to promote tumor growth during lung cancer oncogenesis. Several lines of evidence have suggested that alterations in chromatin remodeling components contribute to cancer initiation and progression. In this study, we identified SMARCD1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily d, member 1) as a novel target gene of miR-7. miR-7 expression reduced SMARCD1 protein expression in lung cancer cell lines. We used luciferase reporters carrying wild type or mutated 3'UTR of SMARCD1 and found that miR-7 blocked SMARCD1 expression by binding to two seed regions in the 3'UTR of SMARCD1 and down-regulated SMARCD1 mRNA expression. Additionally, upon chemotherapy drug treatment, miR-7 down-regulated p53-dependent apoptosis-related gene BAX (BCL2-associated X protein) and p21 expression by interfering with the interaction between SMARCD1 and p53, thereby reducing caspase3 cleavage and the downstream apoptosis cascades. We found that although SMARCD1 sensitized lung cancer cells to chemotherapy drug-induced apoptosis, miR-7 enhanced the drug resistance potential of lung cancer cells against chemotherapy drugs. SMARCD1 was down-regulated in patients with non-small cell lung cancer and lung adenocarcinoma cell lines, and SMARCD1 and miR-7 expression levels were negatively correlated in clinical samples. Our investigation into the involvement of the EGFR-regulated microRNA pathway in the SWI/SNF chromatin remodeling complex suggests that EGFR-mediated miR-7 suppresses the coupling of the chromatin remodeling factor SMARCD1 with p53, resulting in increased chemo-resistance of lung cancer cells.
authors.affiliation: From the Department of Long Term Care, National Quemoy University, Kinmen County 89250.
authors.forename: Chun-Fu
authors.initials: CF
authors.lastname: Hong
authors.affiliation: the National Research Program for Genomic Medicine Core Facilities for Proteomics and Glycomics, Institute of Biological Chemistry, Academia Sinica, Taipei 11529.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.affiliation: the Institute of Biotechnology, National Tsing Hua University, HsinChu 30013,. Electronic address: ytchou@life.nthu.edu.tw.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Chou
authors.affiliation: the Institute of Clinical Medicine,; Institute of Biochemistry and Molecular Biology, and; Institute of Microbiology and Immunology, National Yang Ming University, Taipei 11221, and; the Institute of Biomedical Science, Academia Sinica, Taipei 11221, Taiwan. Electronic address: cwwu@ym.edu.tw.
authors.forename: Cheng-Wen
authors.initials: CW
authors.lastname: Wu
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D035683:MicroRNAs; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C549242:MIRN7-1 microRNA, human; C109786:SMARCD1 protein, human; C495901:TP53 protein, human
keywords: SMARCD1; drug resistance; epidermal growth factor receptor (EGFR); lung cancer; microRNA (miRNA); p53