A 4.1B-PRMT3-UHRF1/DNMT1 Signaling Axis Promotes GBM Brain Tumour Stem Cell Growth

Protein arginine methyltransferase 3 (PRMT3), a type I family PRMT, regulates the activity of downstream substrates by catalyzing the asymmetric dimethylation of arginine residues. While PRMT3 activity has been reported to be deregulated in many cancers, including glioblastoma (GBM), the underlying signaling mechanisms which contribute to disease progression are largely unknown. Here, we show that expression of the tumour suppressor protein 4.1B, a negative regulator of PRMT3, predicts the response of GBM brain tumour stem cells (BTSCs) to the PRMT3 chemical probe, SGC707. We show that PRMT3 modulates the stability and subcellular localization of the downstream effector, UHRF1, a member of the DNA methylation complex. Together, UHRF1 and DNMT1, may suppress the expression of 4.1B through promoter methylation. These findings show that 4.1B, PRMT3 and UHRF1/DNMT1 function together to promote BTSCs growth. Thus, targeting PRMT3 or UHRF1/DNMT1, especially in tumours with low endogenous 4.1B protein, may have high therapeutic relevance.