Browsing by Author "Almeida-Rios, Diogo"
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- Histone methyltransferase PRMT6 plays an oncogenic role of in prostate cancerPublication . Almeida-Rios, Diogo; Pinho dos Santos Graça, Maria Inês; Quintela Vieira, Ana Filipa; Ramalho-Carvalho, João; Pereira-Silva, Eva; Martins, Ana Teresa; Oliveira, Jorge; Gonçalves, Céline S.; Costa, Bruno M.; Henrique, Rui; Jerónimo, CarmenProstate cancer (PCa) is a major cause of morbidity and mortality. Until now the specific role of histone methyltransferases (HMTs) deregulated expression/activity in PCa is poorly understood. Herein we aimed to uncover the potential oncogenic role of PRMT6 in prostate carcinogenesis. PRMT6 overexpression was confirmed in PCa, at transcript and protein level. Stable PRMT6 knockdown in PC-3 cells attenuated malignant phenotype, increasing apoptosis and decreasing cell viability, migration and invasion. PRMT6 silencing was associated with decreased H3R2me2a levels and increased MLL and SMYD3 expression. PRMT6 silencing increased p21, p27 and CD44 and decreased MMP-9 expression and was associated with PI3K/AKT/mTOR downregulation and increased AR signaling pathway. In Sh-PRMT6 cells, AR restored expression might re-sensitized cells to androgen deprivation therapy, impacting in clinical management of castration-resistant PCa (CRPC). PRMT6 plays an oncogenic role in PCa and predicts for more clinically aggressive disease, constituting a potential target for patients with CRPC.
- Histone posttranslational modifications and chromatin remodelers in prostate cancerPublication . Quintela Vieira, Ana Filipa; Almeida-Rios, Diogo; Pinho dos Santos Graça, Maria Inês; Henrique, Rui; Jerónimo, CarmenProstate cancer (PCa) is one of the most incident and prevalent cancers in men worldwide and a leading cause of cancer-related morbidity and mortality. Epigenetics plays an important role in prostate carcinogenesis, namely abnormal expression of histone modifier enzymes and related chromatin modifications. Notwithstanding, the limited knowledge of the specific role of deregulated activity/expression of histone modifiers and respective histone modifications hinders their use in clinical management, particularly for PCa detection and prognostication. Due to the limitations in the analysis of global patterns of histone modifications, few studies reported on the biomarker potential of these epigenetic marks. Importantly, the reversible nature of histone modifications makes them a promising therapeutic option for this malignancy. Indeed, over the past years, molecules with inhibitory activity upon the epigenetic machinery have been developed and are currently under evaluation in clinical trials to test their effectiveness.
- SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3Publication . Quintela Vieira, Ana Filipa; Costa-Pinheiro, Pedro; Almeida-Rios, Diogo; Pinho dos Santos Graça, Maria Inês; Reis, Sara; Simões-Sousa, Susana; Carneiro, Isa; Sousa, Elsa Joana; Godinho, Maria Inês; Baltazar, Fatima; Henrique, Rui; Jeronimo, CarmenProstate 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.