The SMARCA4 R1157W mutation accelerates colorectal cancer progression by facilitating SMARCA4 recruitment to H4R3me2a and chromatin remodeling

Background: Genomic studies have demonstrated a high frequency of genetic alterations in components of the SWI/SNF complex including the core subunit SMARCA4. However, the mechanisms of tumorigenesis driven by SMARCA4 mutations, particularly in colorectal cancer (CRC), remain largely unknown. Methods: To reveal the role of the SMARCA4R1157W mutation in CRC cells and its consequences on CRC progression, we used multiple approaches and techniques. These include DNA sequencing, the CRISPR/Cas9 genome editing system, biochemical assays including protein interaction studies, chromatin immunoprecipitation (ChIP) and chromatin remodeling assays, cellular analysis including cell proliferation, colony formation, migration assays and culture of CRC patient-derived organoids, clinical sample analysis and treatment of cell line-derived xenograft (CDX) mouse models. Results: We identified a specific, hotspot mutation in SMARCA4 (c. 3721 C>T) which results in conversion from arginine to tryptophan at residue 1157 (R1157W) in human CRC tissues associated with higher grade tumors and controls CRC progression. Mechanistically, we found that the SMARCA4R1157W mutation facilitated its recruitment to PRMT1-mediated H4R3me2a (asymmetric dimethylation of Arg 3 in histone H4) and enhanced the ATPase activity of SWI/SNF complex to remodel chromatin in CRC cells. We further showed that the SMARCA4R1157W mutant reinforced the transcriptional expression of EGFR and TNS4 to promote proliferation of CRC cells and patient-derived tumor organoids. Importantly, we demonstrated that SMARCA4R1157W CRC cells and mutant cell-derived xenografts were more sensitive to combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Conclusions: Together, our findings show that SMARCA4-R1157W is a novel gain-of-function mutation, which accelerates CRC progression through epigenetic reprograming of EGFR signaling. Our results suggest a novel therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.