SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3
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Filipa Quintela Vieira1,2, Pedro Costa-Pinheiro1,*, Diogo Almeida-Rios1,5,*, Inês Graça1,2, Sara Monteiro-Reis1,5, Susana Simões-Sousa3,4, Isa Carneiro1,5, Elsa Joana Sousa1, Maria Inês Godinho6, Fátima Baltazar3,4, Rui Henrique1,5,7,*,#, Carmen Jerónimo1,7*,#
1Cancer Biology and Epigenetics Group – Research Center, Portuguese Oncology Institute – Porto, Portugal
2School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Portugal
3Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal
4ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
5Departments of Pathology, Portuguese Oncology Institute – Porto, Portugal
6Departments of Immunology, Portuguese Oncology Institute – Porto, Portugal
7Department 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
Carmen Jerónimo, e-mail: firstname.lastname@example.org
Keywords: SMYD3, prostate cancer, histone methyltransferase, SET domain, cyclin D2
Received: November 24, 2014 Accepted: April 13, 2015 Published: April 25, 2015
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.
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