title: H3K9 histone methyltransferase, KMT1E/SETDB1, cooperates with the SMAD2/3 pathway to suppress lung cancer metastasis.
abstract: Aberrant histone methylation is a frequent event during tumor development and progression. KMT1E (also known as SETDB1) is a histone H3K9 methyltransferase that contributes to epigenetic silencing of both oncogenes and tumor suppressor genes in cancer cells. In this report, we demonstrate that KMT1E acts as a metastasis suppressor that is strongly downregulated in highly metastatic lung cancer cells. Restoring KMT1E expression in this setting suppressed filopodia formation, migration, and invasive behavior. Conversely, loss of KMT1E in lung cancer cells with limited metastatic potential promoted migration in vitro and restored metastatic prowess in vivo. Mechanistic investigations indicated that KMT1E cooperates with the TGFβ-regulated complex SMAD2/3 to repress metastasis through ANXA2. Together, our findings defined an essential role for the KMT1E/SMAD2/3 repressor complex in TGFβ-mediated lung cancer metastasis.
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Wu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Jeng-Wei
authors.initials: JW
authors.lastname: Lu
authors.affiliation: Department of Basic Medical Sciences, Center for Cancer Research, College of Veterinary Medicine, Purdue University, West Lafayette, Indiana.
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: I-Hsuan
authors.initials: IH
authors.lastname: Lin
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Da-Liang
authors.initials: DL
authors.lastname: Ou
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Lin
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Kuan-Hsien
authors.initials: KH
authors.lastname: Chou
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Wen-Feng
authors.initials: WF
authors.lastname: Huang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan, Taiwan, Republic of China.
authors.forename: Wan-Ping
authors.initials: WP
authors.lastname: Wang
authors.affiliation: Department of Medical Research, Buddhist Dalin Tzu Chi Hospital, Chiayi, Taiwan, Republic of China.
authors.forename: Yih-Leh
authors.initials: YL
authors.lastname: Huang
authors.affiliation: Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China. Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Chiun
authors.initials: C
authors.lastname: Hsu
authors.affiliation: Department of Clinical Laboratory Sciences and Medical Biotechnology, National Taiwan University, Taipei, Taiwan, Republic of China. Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Liang-In
authors.initials: LI
authors.lastname: Lin
authors.affiliation: Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan, Republic of China.
authors.forename: Yueh-Min
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.
authors.forename: C-K James
authors.initials: CK
authors.lastname: Shen
authors.affiliation: VYM Genome Research Center, National Yang-Ming University, Taipei, Taiwan, Republic of China. tytzeng@ym.edu.tw.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Tzeng
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008745:Methylation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011496:Protein Methyltransferases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C454062:SETDB1 protein, human