PRMT2 links histone H3R8 asymmetric dimethylation to oncogenic activation and tumorigenesis of glioblastoma

Abstract

Transcriptional deregulation has a vital role in glioblastoma multiforme (GBM). Thus, identification of epigenetic modifiers essential for oncogenic transcriptional programs is a key to designing effective therapeutics for this deadly disease. Here we report that Protein Arginine Methyltransferase 2 (PRMT2) is highly expressed in GBM and correlated with poor prognosis. The silencing or inactivation of PRMT2 inhibits GBM cell growth and glioblastoma stem cell self-renewal in vitro, and suppresses orthotopic tumor growth, accompanied with significant deregulation of genes mainly associated with cell cycle progression and pathways in cancer. Mechanistically PRMT2 is responsible for H3R8 asymmetric methylation (H3R8me2a), whose enrichment at promoters and enhancers is closely correlated with known active histone marks and is required for the maintenance of target gene expression. Together, this study demonstrates that PRMT2 acts as a transcriptional co-activator for oncogenic gene expression programs in GBM pathogenesis and provides a rationale for PRMT2 targeting in aggressive gliomas.

Multifaceted WNT Signaling at the Crossroads Between Epithelial-Mesenchymal Transition and Autophagy in Glioblastoma

“…Thus, meArg has been associated with cancer progression and PRMTs have been considered as novel drug targets (68). In GBM, PRMT2 was shown to be overexpressed and is correlated with a poor prognosis (69). PRMT5 is also highly expressed in GBM, promotes self-renewal of GBM neurospheres (70), and resistance to mTOR inhibition in GBM cells lines and short-term patient cultures (71).…”

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

“…Additionally, enrichment of asymmetric dimethylation of H3R8 (H3R8me2a) is associated with known activating histone marks. This finding has implications in GBM tumorigenesis, in that, PRMT2 has been shown to act as a transcriptional co-activator of genes involved in oncogenesis and more specifically, GBM development [ 14 ]. Overexpression of PRMT2 in GBM pathogenesis makes it a potential target for tumor therapy but a potent small molecule inhibitor of PRMT2 has not yet been designed.…”

“…A variety of cancers have been linked to alterations in methyltransferase enzyme activity, including the brain tumors glioblastoma and medulloblastoma. Within the past decade, investigators have increasingly studied the role arginine methylation plays in brain tumors, particularly the relationship of PRMT activity to glioblastoma (GBM) and medulloblastoma development [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Histone methyltransferase and drug resistance in cancers

“…However, it was found that PRMTs have different catalytic sites and catalytic activities, and they are involved in the occurrence and development of a variety of cancers. The overexpression of PRMTs can promote cancer proliferation and metastasis [46][47][48]. For example, PRMT1, the most active member of the PRMTs family, can catalyze methylation of the FMS-like receptor tyrosine kinase 3internal tandem duplication protein at arginine 972/973.…”