Histone methyltransferase PRMT6 plays an oncogenic role of in prostate cancer

// Diogo Almeida-Rios 1, 2, # , Inês Graça 1, 4, # , Filipa Quintela Vieira 1, 4 , João Ramalho-Carvalho 1 , Eva Pereira-Silva 1 , Ana Teresa Martins 1, 2 , Jorge Oliveira 3 , Céline S. Gonçalves 5, 6 , Bruno M. Costa 5, 6 , Rui Henrique 1, 2, 7, * , Carmen Jerónimo 1, 7, * 1 Cancer Biology & Epigenetics Group Research Center, Portuguese Oncology Institute of Porto, Porto, Portugal 2 Department of Pathology, Portuguese Oncology Institute of Porto, Porto, Portugal 3 Department of Urology, Portuguese Oncology Institute of Porto, Porto, Portugal 4 Department of Morphological Sciences, School of Allied Health Sciences (ESTSP), Polytechnic of Porto, Porto, Portugal 5 Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal 6 ICVS/3B's PT Government Associate Laboratory, Braga/Guimarães, Braga, Portugal 7 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal # Joint first authors * Joint senior authors Correspondence to: Carmen Jerónimo, email: carmenjeronimo@ipoporto.min-saude.pt ; cljeronimo@icbas.up.pt Keywords: androgen receptor, histone methyltransferase, PRMT6, prostate cancer Received: September 21, 2015 Accepted: June 01, 2016 Published: June 15, 2016 ABSTRACT 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.