Associação Portuguesa de Investigação em Cancro
SMYD3 contributes to a more aggressive phenotype of prostate cancer
SMYD3 contributes to a more aggressive phenotype of prostate cancer
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*,#
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
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.
Oncotarget
