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Downregulation of miR-130b~301b cluster is mediated by aberrant promoter methylation and impairs cellular senescence in prostate cancer

Publication . Ramalho-Carvalho, João; Pinho dos Santos Graça, Maria Inês; Gomez, Antonio; Oliveira, Jorge; Henrique, Rui; Esteller, Manel; Jerónimo, Carmen

Numerous DNA-damaging cellular stresses, including oncogene activation and DNA-damage response (DDR), may lead to cellular senescence. Previous observations linked microRNA deregulation with altered senescent patterns, prompting us to investigate whether epigenetic repression of microRNAs expression might disrupt senescence in prostate cancer (PCa) cells. Differential methylation mapping in prostate tissues was carried using Infinium HumanMethylation450 BeadChip. After validation of methylation and expression analyses in a larger series of prostate tissues, the functional role of the cluster miR-130b~301b was explored using in vitro studies testing cell viability, apoptosis, invasion and DNA damage in prostate cancer cell lines. Western blot and RT-qPCR were performed to support those observations. We found that the miR-130b~301b cluster directs epigenetic activation of cell cycle inhibitors required for DDR activation, thus stimulating the senescence-associated secretory phenotype (SASP). Furthermore, overexpression of miR-130b~301b cluster markedly reduced the malignant phenotype of PCa cells. Altogether, these data demonstrate that miR-130b~301b cluster overexpression might effectively induce PCa cell growth arrest through epigenetic regulation of proliferation-blocking genes and activation of cellular senescence.

2017Journal article

Open access

Histone methyltransferase PRMT6 plays an oncogenic role of in prostate cancer

Publication . 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, Carmen

Prostate 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.

2016Journal article

Open access