title: Epigenetic silencing of microRNA-373 to epithelial-mesenchymal transition in non-small cell lung cancer through IRAK2 and LAMP1 axes.
abstract: The role of microRNAs (miRNAs) in carcinogenesis as tumor suppressors or oncogenes has been widely reported. Epigenetic change is one of the mechanisms of transcriptional silencing of miRNAs in cancer. To identify lung cancer-related miRNAs that are mediated by histone modification, we conducted microarray analysis in the Calu-6 non-small cell lung cancer (NSCLC) cell line after treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor. The expression level of miR-373 was enhanced by SAHA treatment in this cell line by microarray and the following quantitative RT-PCR analyses. Treatment with another HDAC inhibitor, Trichostatin A, restored the levels of miR-373 expression in A549 and Calu-6 cells, while demethylation drug treatment did not. Importantly, miR-373 was found to be down-regulated in NSCLC tissues and cell lines. Transfection of miR-373 into A549 and Calu-6 cells attenuated cell proliferation, migration, and invasion and reduced the expression of mesenchymal markers. Additional microarray analysis of miR-373-transfected cells and computational predictions identified IRAK2 and LAMP1 as targets of miR-373. Knockdown of these two genes showed similar biological effects to those of miR-373 overexpression. In clinical samples, overexpression of IRAK2 correlated with decreased disease-free survival of patients with non-adenocarcinoma. In conclusion, we found that miR-373 is silenced by histone modification in lung cancer cells and identified its function as a tumor suppressor and negative regulator of the mesenchymal phenotype through downstream IRAK2 and LAMP1 target genes.
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea; Asan Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea.
authors: Hyang Sook
authors: HS
authors: Seol
authors: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors: Yoshimitsu
authors: Y
authors: Akiyama
authors: Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.
authors: Shu
authors: S
authors: Shimada
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea.
authors: Hee Jin
authors: HJ
authors: Lee
authors: Asan Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea.
authors: Tae Im
authors: TI
authors: Kim
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea; Asan Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea.
authors: Sung Min
authors: SM
authors: Chun
authors: Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Electronic address: singhshr@mail.nih.gov.
authors: Shree Ram
authors: SR
authors: Singh
authors: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea; Asan Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center, Seoul 138-736, South Korea. Electronic address: jangsejin@amc.seoul.kr.
authors: Se Jin
authors: SJ
authors: Jang
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051907:Lysosomal Membrane Proteins / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D011499:Protein Processing, Post-Translational; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D006657:Histones; D053592:Interleukin-1 Receptor-Associated Kinases; D051907:Lysosomal Membrane Proteins; D035683:MicroRNAs; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C527114:MIRN373 microRNA, human
keywords: Histone deacetylase; IRAK2; LAMP1; Non-small cell lung cancer; Tumor suppressor; microRNA-373