PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling

Abstract

Background Aberrant changes in epigenetic mechanisms such as histone modifications play an important role in cancer progression. PRMT1 which triggers asymmetric dimethylation of histone H4 on arginine 3 (H4R3me2a) is upregulated in human colorectal cancer (CRC) and is essential for cell proliferation. However, how this dysregulated modification might contribute to malignant transitions of CRC remains poorly understood. Methods In this study, we integrated biochemical assays including protein interaction studies and chromatin immunoprecipitation (ChIP), cellular analysis including cell viability, proliferation, colony formation, and migration assays, clinical sample analysis, microarray experiments, and ChIP-Seq data to investigate the potential genomic recognition pattern of H4R3me2s in CRC cells and its effect on CRC progression. Results We show that PRMT1 and SMARCA4, an ATPase subunit of the SWI/SNF chromatin remodeling complex, act cooperatively to promote colorectal cancer (CRC) progression. We find that SMARCA4 is a novel effector molecule of PRMT1-mediated H4R3me2a. Mechanistically, we show that H4R3me2a directly recruited SMARCA4 to promote the proliferative, colony-formative, and migratory abilities of CRC cells by enhancing EGFR signaling. We found that EGFR and TNS4 were major direct downstream transcriptional targets of PRMT1 and SMARCA4 in colon cells, and acted in a PRMT1 methyltransferase activity-dependent manner to promote CRC cell proliferation. In vivo, knockdown or inhibition of PRMT1 profoundly attenuated the growth of CRC cells in the C57BL/6 J-ApcMin/+ CRC mice model. Importantly, elevated expression of PRMT1 or SMARCA4 in CRC patients were positively correlated with expression of EGFR and TNS4, and CRC patients had shorter overall survival. These findings reveal a critical interplay between epigenetic and transcriptional control during CRC progression, suggesting that SMARCA4 is a novel key epigenetic modulator of CRC. Our findings thus highlight PRMT1/SMARCA4 inhibition as a potential therapeutic intervention strategy for CRC. Conclusion PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling.

A Pan-Cancer Analysis of SMARCA4 Alterations in Human Cancers

“…DNA methylation is an epigenetic mechanism and a novel predictor for tumorigenesis. SMARCA4 is a novel key epigenetic modulator of colorectal cancer (22), and SMARCA4 may directly influence the loss of DNA methylation, which provided insight of aberrant gene induction during tumor progression (23).…”

PRMT1 Regulates EGFR and Wnt Signaling Pathways and Is a Promising Target for Combinatorial Treatment of Breast Cancer

“…Here, we focused on two pathways that are known to be activated in TNBC [ 3 , 4 , 5 ]. PRMT1 has been previously observed to modulate EGFR signaling by two mechanisms: (i) by methylating histone H4 (H4R3me2a) on its promoter in colorectal cancer (CRC) [ 23 ] and glioblastoma cells [ 24 ] and (ii) by methylating EGFR in CRC and TNBC cells [ 20 , 21 ]. Here, we demonstrate that PRMT1 itself is directly recruited to the promoter of EGFR , thus activating its transcription.…”

“…Arginine methylation regulates several cellular processes including transcriptional regulation and signal transduction [ 8 , 11 , 12 ]. PRMT1 and PRMT5 regulate the EGFR signaling pathway by methylating EGFR (in colorectal and TNBC cells) [ 20 , 21 , 22 ], or by methylating histones on the EGFR promoter (in glioblastoma or colorectal cells) [ 23 , 24 ] to regulate its transcription. Furthermore, some PRMTs regulate the canonical Wnt signaling pathway [ 12 ].…”

Structure, Activity, and Function of PRMT1

“…Mechanistically, it was described that H4R3me2a can recruit SMARCA4, an ATPase subunit of the SWI/SNF complex, to the promoter of certain target genes including EGFR to promote their expression. PRMT1dependent enhancing of EGFR signaling is associated with a significant increase in the proliferative and migratory abilities of human CRC cells [156]. Moreover, methylation of EGFR at R198 and R200 by PRMT1 leads to an EGF-dependent hyperactivation of EGFR signaling and confers cells with resistance to the anti-EGFR monoclonal antibody, cetuximab.…”