title: SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3.
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.
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Porto, Portugal.
authors.forename: Filipa Quintela
authors.initials: FQ
authors.lastname: Vieira
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Costa-Pinheiro
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Diogo
authors.initials: D
authors.lastname: Almeida-Rios
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Porto, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Graça
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Sara
authors.initials: S
authors.lastname: Monteiro-Reis
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Simões-Sousa
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Isa
authors.initials: I
authors.lastname: Carneiro
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Elsa Joana
authors.initials: EJ
authors.lastname: Sousa
authors.affiliation: Departments of Immunology, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Maria Inês
authors.initials: MI
authors.lastname: Godinho
authors.affiliation: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.|ICVS/3B's, PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Baltazar
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|Departments of Pathology, Portuguese Oncology Institute, Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.affiliation: Cancer Biology and Epigenetics Group, Research Center, Portuguese Oncology Institute, Porto, Portugal.|Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal.
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002642:Chick Embryo; D056742:Cyclin D2 / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: C080336:CCND2 protein, human; D056742:Cyclin D2; D011495:Histone-Lysine N-Methyltransferase; C506278:SMYD3 protein, human
keywords: SET domain; SMYD3; cyclin D2; histone methyltransferase; prostate cancer