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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.
- Estudo de novos compostos sintéticos para o tratamento do cancro da mamaPublication . Magalhães, Ângela; Vieira, Filipa Quintela; Vieira, Mónica; Ferraz, Ricardo; Prudêncio, Cristina; Jerónimo, Carmen; Silva, ReginaO cancro da mama (CaM) apesar dos avanços no tratamento e deteção precoce desta neoplasia, permanece como uma das principais causas de morte por cancro nas mulheres devido à progressão e disseminação sistémica. Cerca de 80% dos CaM invasivos são positivos para o recetor de estrogénios sendo candidatos à terapia de bloqueio. No entanto, 30- 40% das doentes desenvolvem recidiva, evoluindo para um fenótipo hormono-resistente. Nestes estadios, as opções terapêuticas apresentam uma reduzida eficácia. Assim, é importante a descoberta de novos agentes anti-neoplásicos. Os líquidos iónicos e as quinoxalinas são sais orgânicos com potencial anti-tumoral que têm vindo a ser alvo de estudo na indústria farmacêutica devido às suas propriedades medicinais e composição flexível no caso dos líquidos iónicos.
- Expression of histone methyltransferases as novel biomarkers for renal cell tumor diagnosis and prognosticationPublication . Pires-Luís, Ana Sílvia; Vieira-Coimbra, Marcia; Quintela Vieira, Ana Filipa; Costa-Pinheiro, Pedro; Silva-Santos, Rui; Dias, Paula C; Antunes, Luís; Lobo, Francisco; Oliveira, Jorge; Gonçalves, Céline S; Costa, Bruno M; Henrique, Rui; Jerónimo, CarmenRenal cell tumors (RCTs) are the most lethal of the common urological cancers. The widespread use of imaging entailed an increased detection of small renal masses, emphasizing the need for accurate distinction between benign and malignant RCTs, which is critical for adequate therapeutic management. Histone methylation has been implicated in renal tumorigenesis, but its potential clinical value as RCT biomarker remains mostly unexplored. Hence, the main goal of this study was to identify differentially expressed histone methyltransferases (HMTs) and histone demethylases (HDMs) that might prove useful for RCT diagnosis and prognostication, emphasizing the discrimination between oncocytoma (a benign tumor) and renal cell carcinoma (RCC), especially the chromophobe subtype (chRCC). We found that the expression levels of 3 genes--SMYD2, SETD3, and NO66--was significantly altered in a set of RCTs, which was further validated in a large independent cohort. Higher expression levels were found in RCTs compared to normal renal tissues (RNTs) and in chRCCs comparatively to oncocytomas. SMYD2 and SETD3 mRNA levels correlated with protein expression assessed by immunohistochemistry. SMYD2 transcript levels discriminated RCTs from RNT, with 82.1% sensitivity and 100% specificity [area under curve (AUC) = 0.959], and distinguished chRCCs from oncocytomas, with 71.0% sensitivity and 73.3% specificity (AUC = 0.784). Low expression levels of SMYD2, SETD3, and NO66 were significantly associated with shorter disease-specific and disease-free survival, especially in patients with non-organ confined tumors. We conclude that expression of selected HMTs and HDMs might constitute novel biomarkers to assist in RCT diagnosis and assessment of tumor aggressiveness.
- Impact of different storage conditions of formamide in the quality of sequencesPublication . Moura, Daniela; Pina, Maria João; Pereira, Cátia; Baixia, Márcia; Leal, Rafaela; Sousa, Sónia; Vieira, Filipa Quintela; Silva, Regina; Cirnes, LuísObtaining high quality sequences is essential to proper reading and interpretation. A crucial step for this goal is the denaturation of sequencing products which is usually performed using a denaturing agent such as formamide. It has been described that the reduction of formamide quality may cause irregular cytosine and guanine peaks in an electropherogram.According to manufacturers recomendations, formamide should be stored at -20ºC. Under other conditions such as exposition to light and air and temperature changes for a certain period of time, quality may decrease. Objectives: The purpose of this study was to understand which formamide storage-related variables can be responsible for decreasing sequence quality.
- Phenotypic impact of deregulated expression of class I histone deacetylases in urothelial cell carcinoma of the bladderPublication . Neto, Susana; Quintela Vieira, Ana Filipa; Montezuma, Diana; Costa, Natália R.; Antunes, Luís; Baptista, Tiago; Oliveira, Ana Isabel; Pinho dos Santos Graça, Maria Inês; Rodrigues, Ângelo; Magalhães, José S.; Oliveira, Jorge; Henrique, Rui; Jerónimo, CarmenDeregulated expression of histone deacetylases (HDACs) has been implicated in tumorigenesis. Herein, we investigated class I HDACs expression in bladder urothelial cell carcinoma (BUCC), its prognostic value and biological significance. Significantly increased transcript levels of all HDACs were found in BUCC compared to 20 normal mucosas, and these were higher in lower grade and stage tumors. Increased HDAC3 levels were associated with improved patient survival. SiRNA experiments showed decrease cell viability and motility, and increased apoptosis. We concluded that class I HDACs play an important role in bladder carcinogenesis through deregulation of proliferation, migration and apoptosis, constituting putative therapeutic targets.
- 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.
- Atividade citotóxica de extratos de Taraxacum hispanicum em linhas celulares de cancro da mamaPublication . Magalhães, Ângela; Vieira, Filipa Quintela; Pinho, Cláudia; Oliveira, Ana; Cruz, Agostinho; Carmen, Jerónimo; Silva, ReginaAs plantas do género Taraxacum têm sido utilizadas tradicionalmente em tratamentos por apresentarem propriedades diuréticas, antioxidantes, anti-inflamatórias, hepatoprotetoras e antitumorais. O cancro da mama é um dos cancros mais comuns em Portugal, particularmente na região norte do país. Cerca de 75-80% dos casos de cancro da mama invasivo expressam recetores de estrogénio (RE), tendo uma boa resposta a terapias antiestrogénica. Contudo, uma parte destes tumores tornam-se estrogénio resistentes (ER), sendo os tratamentos utilizados para este tipo de tumores, assim como para o cancro metastático e/ ou recorrente, pouco efetivos. Assim, é necessário pesquisar novas alternativas terapêuticas seguras e eficazes.
- Taraxacum spp. in vitro and in vivo anticancer activity – a reviewPublication . Oliveira, Ana Isabel; Pinho, Cláudia; Quintela Vieira, Ana Filipa; Silva, Regina; Cruz, AgostinhoCancer is one of the major causes of death universally. Conventional chemotherapeutic agents are associated with severe side effects which limit their general acceptability and leads to a search for alternative efficient and safe options. Plants have been used for centuries as medicinal agents in the treatment of several diseases, including cancer. Dandelion is a plant of the genus Taraxacum and a member of the Asteraceae family with worldwide distribution. It has been used in traditional medicine for the treatment of various disorders, such as gastrointestinal and kidney diseases, dyspepsia, Diabetes mellitus, pneumonia and cancer. The present review aims to provide a comprehensive summary of the main biologically active compounds of dandelion, gathering and describing the information about its anticancer activity. Several in vitro and in vivo studies have demonstrated the cytotoxic ability of Taraxacum species, which can be possibly explained by the complexity and diversity of its phytochemical profile. Therefore, dandelion may have the potential to become an effective chemotherapeutic agent despite the need for further studies.
- Anti-neoplastic properties of hydralazine in prostate cancerPublication . Pinho dos Santos Graça, Maria Inês; Sousa, Elsa Joana; Costa-Pinheiro, Pedro; Quintela Vieira, Ana Filipa; Torres-Ferreira, Jorge; Martins, Maria Gabriela; Henrique, Rui; Jeronimo, CarmenProstate cancer (PCa) is a major cause of cancer-related morbidity and mortality worldwide. Although early disease is often efficiently managed therapeutically, available options for advanced disease are mostly ineffective. Aberrant DNA methylation associated with gene-silencing of cancer-related genes is a common feature of PCa. Therefore, DNA methylation inhibitors might constitute an attractive alternative therapy. Herein, we evaluated the anti-cancer properties of hydralazine, a non-nucleoside DNA methyltransferases (DNMT) inhibitor, in PCa cell lines. In vitro assays showed that hydralazine exposure led to a significant dose and time dependent growth inhibition, increased apoptotic rate and decreased invasiveness. Furthermore, it also induced cell cycle arrest and DNA damage. These phenotypic effects were particularly prominent in DU145 cells. Following hydralazine exposure, decreased levels of DNMT1, DNMT3a and DNMT3b mRNA and DNMT1 protein were depicted. Moreover, a significant decrease in GSTP1, BCL2 and CCND2 promoter methylation levels, with concomitant transcript re-expression, was also observed. Interestingly, hydralazine restored androgen receptor expression, with upregulation of its target p21 in DU145 cell line. Protein array analysis suggested that blockage of EGF receptor signaling pathway is likely to be the main mechanism of hydralazine action in DU145 cells. Our data demonstrate that hydralazine attenuated the malignant phenotype of PCa cells, and might constitute a useful therapeutic tool.
- Effects of different storage conditions of sequencing products with formamide in the quality of sequences.Publication . Moura, Daniela; Pina, Maria João; Pereira, Cátia; Baixia, Márcia; Leal, Rafaela; Sousa, Sónia; Vieira, Filipa Quintela; Silva, Regina; Cirnes, LuísDNA sequencing is widely used in molecular diagnosis and good sequence quality is crucial to a correct interpretation. It has been described that formamide quality decrease and sequencing reactions exposure to light, heat and/or oxygen can cause irregular peaks of cytosine and guanine in electropherograms. In a previous study, we concluded that despite the presence of this artifact when formamide is stored under non-ideal conditions, it does not significantly reduce the quality of the sequences.
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