The Protein Arginine Methyltransferases 1 and 5 affect Myc properties in glioblastoma stem cells

Abstract

Protein Arginine (R) methylation is the most common post-translational methylation in mammalian cells. Protein Arginine Methyltransferases (PRMT) 1 and 5 dimethylate their substrates on R residues, asymmetrically and symmetrically, respectively. They are ubiquitously expressed and play fundamental roles in tumour malignancies, including glioblastoma multiforme (GBM) which presents largely deregulated Myc activity. Previously, we demonstrated that PRMT5 associates with Myc in GBM cells, modulating, at least in part, its transcriptional properties. Here we show that Myc/PRMT5 protein complex includes PRMT1, in both HEK293T and glioblastoma stem cells (GSCs). We demonstrate that Myc is both asymmetrically and symmetrically dimethylated by PRMT1 and PRMT5, respectively, and that these modifications differentially regulate its stability. Moreover, we show that the ratio between symmetrically and asymmetrically dimethylated Myc changes in GSCs grown in stem versus differentiating conditions. Finally, both PRMT1 and PRMT5 activity modulate Myc binding at its specific target promoters. To our knowledge, this is the first work reporting R asymmetrical and symmetrical dimethylation as novel Myc post-translational modifications, with different functional properties. This opens a completely unexplored field of investigation in Myc biology and suggests symmetrically dimethylated Myc species as novel diagnostic and prognostic markers and druggable therapeutic targets for GBM.

PRMT1 promotes neuroblastoma cell survival through ATF5

“…The mechanistic interplay between aDMA and sDMA of MYCN is currently unclear, but it appears that a certain threshold of arginine methylation regardless of whether it is aDMA or sDMA is required for cell survival, as demonstrated by induction of cell apoptosis in cells depleted of either PRMT1 or PRMT5 through RNA interference 3,4 . This idea is supported by a recent report showing that MYC is both asymmetrically and symmetrically dimethylated by PRMT1 and PRMT5, respectively, with different functional properties in glioblastoma 30 . Second, the high potency of decamidine we observed in our current study may be due to combined PRMT1 and PRMT5 inhibition.…”

Combining protein arginine methyltransferase inhibitor and anti-programmed death-ligand-1 inhibits pancreatic cancer progression

“…Our study results showed that PRMT1 downregulation was correlated with PD-L1 downregulation in PDAC tumors. Studies suggest that PRMT1 regulates c-myc gene expression and function[ 32 , 33 ]. Current data show that c-myc , an important signaling hub and driver gene, is commonly overexpressed and aberrantly activated in PDAC[ 34 , 35 ].…”

Splicing Dysregulation as Oncogenic Driver and Passenger Factor in Brain Tumors

“…In this regard, a promising target is PRMT5, a type II methyltransferase that is responsible for depositing the majority of the symmetrical dimethylation marks on arginines (SDMA) and methylates several RNA binding proteins and spliceosomal proteins [133][134][135]. In MYC-driven tumors, PRMT5 enhances assembly of spliceosome components and MYC expression [136,137]. Since MYC promotes GBM cell survival, proliferation, invasiveness, and self-renewal, its expression is inversely correlated with patient survival [53,[138][139][140].…”