title: SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation.
abstract: SMYD3 methyltransferase is nearly undetectable in normal human tissues but highly expressed in several cancers, including breast cancer, although its contributions to pathogenesis in this setting are unclear. Here we report that histone H2A.Z.1 is a substrate of SMYD3 that supports malignancy. SMYD3-mediated dimethylation of H2A.Z.1 at lysine 101 (H2A.Z.1K101me2) increased stability by preventing binding to the removal chaperone ANP32E and facilitating its interaction with histone H3. Moreover, a microarray analysis identified cyclin A1 as a target coregulated by SMYD3 and H2A.Z.1K101me2. The colocalization of SMYD3 and H2A.Z.1K101me2 at the promoter of cyclin A1 activated its expression and G1-S progression. Enforced expression of cyclin A1 in cells containing mutant H2A.Z.1 rescued tumor formation in a mouse model. Our findings suggest that SMYD3-mediated H2A.Z.1K101 dimethylation activates cyclin A1 expression and contributes to driving the proliferation of breast cancer cells. Cancer Res; 76(20); 6043-53. ©2016 AACR.
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Cheng-Hui
authors: CH
authors: Tsai
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Yun-Ju
authors: YJ
authors: Chen
authors: Department of Cell and Molecular Biology, Chang Gung University, Tao-Yuan, Taiwan. Department of Thoracic Medicine, Chang Gung Memorial Hospital, Linkou, Tao-Yuan, Taiwan.
authors: Chia-Jung
authors: CJ
authors: Yu
authors: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Shiou-Ru
authors: SR
authors: Tzeng
authors: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: I-Chen
authors: IC
authors: Wu
authors: Department of Surgery, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Wen-Hung
authors: WH
authors: Kuo
authors: Department of Pathology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Ming-Chieh
authors: MC
authors: Lin
authors: Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Nei-Li
authors: NL
authors: Chan
authors: Research Center for Tumor Medical Science, Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan.
authors: Kou-Juey
authors: KJ
authors: Wu
authors: Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan. shuchunteng@ntu.edu.tw.
authors: Shu-Chun
authors: SC
authors: Teng
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056750:Cyclin A1 / Q000235:genetics; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000502:physiology*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D051379:Mice
chemical_list: C503747:Ccna1 protein, mouse; D056750:Cyclin A1; C000611883:H2az1 protein, mouse; D006657:Histones; D011495:Histone-Lysine N-Methyltransferase; C582787:Smyd3 protein, mouse