CRISPR/Cas9 screenings unearth protein arginine methyltransferase 7 as a novel driver of metastasis in prostate cancer

Abstract

ABSTRACTOwing to the inefficacy of available treatments, the survival rate of patients with metastatic prostate cancer (mPCa) is severely decreased. Therefore, it is crucial to identify new therapeutic targets to increase their survival. This study aim was to identify the most relevant regulators of mPCa onset by performing two high-throughput CRISPR/Cas9 screenings. Furthermore, some of the top hits were validated using small interfering RNA (siRNA) technology, with protein arginine methyltransferase 7(PRMT7)being the best candidate. Its inhibition or depletion via CRISPR significantly reduced mPCa cell capacitiesin vitro. Moreover,PRMT7ablation reduced mPCa appearance in chicken chorioallantoic membrane and mouse xenograft assays. Molecularly, PRMT7 reprograms the expression of several adhesion molecules through methylation of several transcription factors, such as FoxK1 or NR1H2, which results in primary tumor PCa cell adhesion loss and motility gain. Importantly,PRMT7is upregulated in advanced stages of Spanish PCa tumor samples and PRMT7 pharmacological inhibition reduces the dissemination of mPCa cells. Thus, here is shown thatPRMT7is a potential therapeutic target and biomarker of mPCa.