基因组学研究表明，包括核心亚单位SMARCA4在内的SWI/SNF复合物中遗传改变的频率很高。然而，SMARCA4突变驱动的肿瘤发生机制，尤其是在结直肠癌（CRC）中，仍然大多数未知。在本研究中，我们在与高级别肿瘤和控制CRC进展有关的人类CRC组织中鉴定了SMARCA4的一个特定的热点突变（c.3721C>T），该突变导致在残基1157处从精氨酸转变为色氨酸（R1157W）。从机理上讲，我们发现SMARCA4R1157W突变促进了其对PRMT1介导的H4R3me2a（组蛋白H4中Arg 3的不对称二甲基化）的募集，并增强了SWI/SNF复合物的ATP酶活性以在CRC细胞中重构染色质。我们进一步显示，SMARCA4R1157W突变体加强了EGFR和TNS4的转录表达以促进CRC细胞和来自患者的肿瘤器官样细胞的增殖。重要的是，我们证明了SMARCA4R1157W CRC细胞和突变体细胞源性异种移植瘤对PRMT1和SMARCA4的联合抑制更为敏感，二者协同抑制细胞增殖。综上所述，我们的发现表明SMARCA4-R1157W是一种重要的活化突变体，通过促进染色质募集和重构加速CRC的进展。我们的结果为携带SMARCA4R1157W突变的CRC患者提供了潜在的精准治疗策略。 ©2023。作者（们）。

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. In this study, we identified a specific, hotspot mutation in SMARCA4 (c. 3721C>T) which results in a 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 the 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 the combined inhibition of PRMT1 and SMARCA4 which act synergistically to suppress cell proliferation. Together, our findings show that SMARCA4-R1157W is a critical activating mutation, which accelerates CRC progression through facilitating chromatin recruitment and remodeling. Our results suggest a potential precision therapeutic strategy for the treatment of CRC patients carrying the SMARCA4R1157W mutation.© 2023. The Author(s).