RESUMO
Post-translational modification (PTM) of proteins is vital for increasing proteome diversity and maintaining cellular homeostasis. If the writing, reading, and removal of modifications are not controlled, cancer can develop. Arginine methylation is an understudied modification that is increasingly associated with cancer progression. Consequently protein arginine methyltransferases (PRMTs), the writers of arginine methylation, have rapidly gained interest as novel drug targets. However, for clinical success a deep mechanistic understanding of the biology of PRMTs is required. In this review we focus on advances made regarding the role of PRMTs in stem cell biology, epigenetics, splicing, immune surveillance and the DNA damage response, and highlight the rapid rise of specific inhibitors that are now in clinical trials for cancer therapy.
Assuntos
Arginina/metabolismo , Metilação , Neoplasias/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Antineoplásicos/farmacologia , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/fisiologia , Resistência a Medicamentos/efeitos dos fármacos , Epigenômica , Histonas/metabolismo , Humanos , Imunoterapia , Camundongos , Terapia de Alvo Molecular/tendências , Neoplasias/tratamento farmacológico , Processamento de Proteína Pós-Traducional/fisiologia , Processamento de Proteína/efeitos dos fármacos , Processamento de Proteína/fisiologia , Proteína-Arginina N-Metiltransferases/metabolismo , Splicing de RNA/efeitos dos fármacos , Splicing de RNA/fisiologia , Células-Tronco/efeitos dos fármacos , Células-Tronco/fisiologiaRESUMO
Breast cancer progression, treatment resistance, and relapse are thought to originate from a small population of tumor cells, breast cancer stem cells (BCSCs). Identification of factors critical for BCSC function is therefore vital for the development of therapies. Here, we identify the arginine methyltransferase PRMT5 as a key in vitro and in vivo regulator of BCSC proliferation and self-renewal and establish FOXP1, a winged helix/forkhead transcription factor, as a critical effector of PRMT5-induced BCSC function. Mechanistically, PRMT5 recruitment to the FOXP1 promoter facilitates H3R2me2s, SET1 recruitment, H3K4me3, and gene expression. Our findings are clinically significant, as PRMT5 depletion within established tumor xenografts or treatment of patient-derived BCSCs with a pre-clinical PRMT5 inhibitor substantially reduces BCSC numbers. Together, our findings highlight the importance of PRMT5 in BCSC maintenance and suggest that small-molecule inhibitors of PRMT5 or downstream targets could be an effective strategy eliminating this cancer-causing population.
