PRMT1 loss sensitizes cells to PRMT5 inhibition

Abstract

PRMT5 is an arginine methyltransferase that accounts for the vast majority of the symmetric methylation in cells. PRMT5 exerts its function when complexed with MEP50/WDR77. This activity is often elevated in cancer cells and correlates with poor prognosis, making PRMT5 a therapeutic target. To investigate the PRMT5 signaling pathway and to identify genes whose loss-of-function sensitizes cancer cells to PRMT5 inhibition, we performed a CRISPR/Cas9 genetic screen in the presence of a PRMT5 inhibitor. We identified known components of the PRMT5 writer/reader pathway including PRMT5 itself, MEP50/WDR77, PPP4C, SMNDC1 and SRSF3. Interestingly, loss of PRMT1, the major asymmetric arginine methyltransferase, also sensitizes cells to PRMT5 inhibition. We investigated the interplay between PRMT5 and PRMT1, and found that combinatorial inhibitor treatment of small cell lung cancer and pancreatic cancer cell models have a synergistic effect. Furthermore, MTAP -deleted cells, which harbor an attenuated PRMT5–MEP50 signaling pathway, are generally more sensitive to PRMT1 inhibition. Together, these findings demonstrate that there is a degree of redundancy between the PRMT5 and PRMT1 pathways, even though these two enzymes deposit different types of arginine methylation marks. Targeting this redundancy provides a vulnerability for tumors carrying a co-deletion of MTAP and the adjacent CDKN2A tumor suppressor gene.

PRMT1 promotes neuroblastoma cell survival through ATF5

“…In good agreement with previous studies, we observed in multiple and diverse PRMT1-depleted human neuroblastoma cell lines an increase of sDMA levels along with the expected decrease of aDMA levels, with no detectable change of PRMT5 protein level (Supplementary Figure S3A-E). This observation is consistent with the notion that loss of PRMT1 activity impacts substrate protein function by switching to a different methylation type mediated by PRMT5 22,23 . Indeed, recent studies have demonstrated a redundancy between PRMT1 and PRMT5 pathways and synergistic anti-tumor effects of combined inhibition of both PRMTs [23][24][25] .…”

“…This observation is consistent with the notion that loss of PRMT1 activity impacts substrate protein function by switching to a different methylation type mediated by PRMT5 22,23 . Indeed, recent studies have demonstrated a redundancy between PRMT1 and PRMT5 pathways and synergistic anti-tumor effects of combined inhibition of both PRMTs [23][24][25] . In the context of neuroblastoma, knockdown of only PRMT1 or PRMT5 leads to cell apoptosis (Fig.…”

Methylthioadenosine is Not Dramatically Elevated inMTAP-Homozygous Deleted Primary Glioblastomas

“…We initially embarked on this study in response to the exigence of MTAP-deleted precision therapy endeavors despite lack of exploration of the metabolic state of primary tumors. As the efficacy of MTAP-deletion directed therapies hinges on massive intracellular accumulation of MTA (Fedoriw et al, 2019;Gao et al, 2019;Hörmann et al, 2018;Kryukov et al, 2016;Marjon et al, 2016;Mavrakis et al, 2016), ensuring that this in vitro phenotype is consistent in human tumors seemed to be a natural and urgent area for investigation. Perhaps surprisingly, none of the recent papers documenting MTAPdependent vulnerabilities actually reported measurements of MTA in primary human tumors or even xenographed tumors of defined MTAP-deletion status, despite the significant efforts that have been built on the supposition that observed elevations in MTA in vitro would be reflected in primary tumors (Fedoriw et al, 2019;Gao et al, 2019;Hörmann et al, 2018;Kryukov et al, 2016;Marjon et al, 2016;Mavrakis et al, 2016).…”

“…Because putrescine is minimally toxic (LD50, > 500 mg/kg; TOXNET CASRN: 110-60-1), it could potentially be used pharmacologically for the deliberate exaggeration of MTA accumulation in MTAP-deleted tumors. (Marjon et al, 2016)), inhibitors or PRMT5 (Hörmann et al, 2018;Mavrakis et al, 2016) and even to PRMT1 (Fedoriw et al, 2019;Gao et al, 2019)…”

Robust detection of oncometabolic aberrations by1H-13C heteronuclear single quantum correlation in live cells and intact tumorsex-vivo

“…Metabolic vulnerabilities are emerging as viable therapeutic targets within the framework of precision oncology [1][2][3] . Well-studied examples of such aberrations include tumors that have mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes.…”