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SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3

2015; Impact Journals LLC; Volume: 6; Issue: 15 Linguagem: Inglês

10.18632/oncotarget.3767

1949-2553

Filipa Quintela Vieira, Pedro Costa‐Pinheiro, Diogo Almeida-Rios, Inês Graça, Sara Monteiro‐Reis, Susana Simoes‐Sousa, Isa Carneiro, Elsa Sousa, M.I. Godinho, Fátima Baltazar, Rui Henrique, Cármen Jerónimo,

Prostate Cancer Treatment and Research

// Filipa Quintela Vieira 1, 2 , Pedro Costa-Pinheiro 1, * , Diogo Almeida-Rios 1, 5, * , Inês Graça 1, 2 , Sara Monteiro-Reis 1, 5 , Susana Simões-Sousa 3, 4 , Isa Carneiro 1, 5 , Elsa Joana Sousa 1 , Maria Inês Godinho 6 , Fátima Baltazar 3, 4 , Rui Henrique 1, 5, 7, *, # , Carmen Jerónimo 1, 7 *, # 1 Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute – Porto, Portugal 2 School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Portugal 3 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal 4 ICVS/3B's - PT Government Associate Laboratory, Braga/Guimarães, Portugal 5 Departments of Pathology, Portuguese Oncology Institute – Porto, Portugal 6 Departments of Immunology, Portuguese Oncology Institute – Porto, Portugal 7 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS) – University of Porto, Portugal * These authors have contributed equally to this work # These authors share senior authorship Correspondence to: Carmen Jerónimo, e-mail: carmenjeronimo@ipoporto.min-saude.pt Keywords: SMYD3, prostate cancer, histone methyltransferase, SET domain, cyclin D2 Received: November 24, 2014 Accepted: April 13, 2015 Published: April 25, 2015 ABSTRACT Prostate cancer (PCa) is one of the most incident cancers worldwide but clinical and pathological parameters have limited ability to discriminate between clinically significant and indolent PCa. Altered expression of histone methyltransferases and histone methylation patterns are involved in prostate carcinogenesis. SMYD3 transcript levels have prognostic value and discriminate among PCa with different clinical aggressiveness, so we decided to investigate its putative oncogenic role on PCa. We silenced SMYD3 and assess its impact through in vitro (cell viability, cell cycle, apoptosis, migration, invasion assays) and in vivo (tumor formation, angiogenesis). We evaluated SET domain's impact in PCa cells' phenotype. Histone marks deposition on SMYD3 putative target genes was assessed by ChIP analysis. Knockdown of SMYD3 attenuated malignant phenotype of LNCaP and PC3 cell lines. Deletions affecting the SET domain showed phenotypic impact similar to SMYD3 silencing, suggesting that tumorigenic effect is mediated through its histone methyltransferase activity. Moreover, CCND2 was identified as a putative target gene for SMYD3 transcriptional regulation, through trimethylation of H4K20. Our results support a proto-oncogenic role for SMYD3 in prostate carcinogenesis, mainly due to its methyltransferase enzymatic activity. Thus, SMYD3 overexpression is a potential biomarker for clinically aggressive disease and an attractive therapeutic target in PCa.