CARM1-mediated methylation of ASXL2 impairs tumor-suppressive function of MLL3/COMPASS

Abstract

An imbalance in the activities of the Polycomb and Trithorax complexes underlies numerous human pathologies, including cancer. The BRCA1 associated protein-1 (BAP1) deubiquitinase negatively regulates Polycomb activity and recruits the Trithorax histone H3K4 methyltransferase, mixed-lineage leukemia protein 3 (MLL3) within Complex Proteins Associated with Set1 (COMPASS), to the enhancers of tumor suppressor genes. We previously demonstrated that the BAP1-MLL3 pathway is mutated in several cancers, yet how BAP1 recruits MLL3 to its target loci remains an important unanswered question. We demonstrate that the ASXL2 subunit of the BAP1 complex mediates a direct interaction with MLL3/COMPASS. ASXL2 loss results in decreased MLL3 occupancy at enhancers and reduced BAP1-MLL3 target gene expression. Interaction between ASXL2 and MLL3 is negatively regulated by protein arginine methyltransferase 4 (PRMT4/CARM1), which methylates ASXL2 at R639/R641. ASXL2 methylation blocks binding to MLL3 and impairs the expression of MLL3/COMPASS-dependent genes. This previously unidentified transcriptional repressive function of CARM1 provides insight into the BAP1/MLL3-COMPASS axis and reveals a potential cancer therapeutic target.

Loss of cohesin regulator PDS5A reveals repressive role of Polycomb loops

“…The top hits in our screen included genes encoding subunits of cPRC1 ( Cbx7, Ring1b ) and PRC2 ( Ezh2 , Suz12 , Eed ), as well as a negative regulator ( Carm1 ) of the Polycomb repressive deubiquitinase complex (PR-DUB) 34 . This indicates that our screening approach identified known genes required for TetR-CBX7-induced silencing ( Cbx7 ) and its epigenetic maintenance ( Ring1b, Suz12, Carm1 ) (Fig.…”

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

“…However, recent evidence suggests that CARM1 can directly add a methyl group to ASXL2 at R639/R641, which subsequently prevents MLL3 from binding to enhancer chromatin, resulting in the repression of nearby genes. 247 In addition to its role in gene transcription, CARM1 regulates various metabolic pathways in different types of cancers, such as oxidative phosphorylation in breast cancer cells, 248 glycolysis in liver cancer cells, 249 and glutamine metabolism in pancreatic cancer (PDAC) cells. 250 For example, PKM2 methylation by CARM1 shifts the balance of metabolism from oxidative phosphorylation to aerobic glycolysis in breast cancer cells.…”

“…Initially, it was proposed that CARM1 functions as a transcriptional activator by adding a methyl group to histone H3R17. However, recent evidence suggests that CARM1 can directly add a methyl group to ASXL2 at R639/R641, which subsequently prevents MLL3 from binding to enhancer chromatin, resulting in the repression of nearby genes 247 . In addition to its role in gene transcription, CARM1 regulates various metabolic pathways in different types of cancers, such as oxidative phosphorylation in breast cancer cells, 248 glycolysis in liver cancer cells, 249 and glutamine metabolism in pancreatic cancer (PDAC) cells 250 .…”

Dysregulation of arginine methylation in tumorigenesis

“…PRMT4 specifically modifies additional sex combs like 2 at residue 639/641 through methylation, resulting in a diminished tumor inhibitory function of the mixed lineage leukemia protein 3 ( Zhao et al, 2022 ). Several independent research efforts have uncovered that PRMT5 plays a pivotal role in the regulation of genes that either stimulate or suppress tumor growth.…”