The SMARCA4(R1157W) mutation facilitates chromatin remodeling and confers PRMT1/SMARCA4 inhibitors sensitivity in colorectal cancer.
The SMARCA4(R1157W) mutation facilitates chromatin remodeling and confers PRMT1/SMARCA4 inhibitors sensitivity in colorectal cancer.
复制标题
DOI：
10.1038/s41698-023-00367-y
复制
发表时间：
2023-03-15
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
--
作者：
基因组研究表明，SWI/SNF复合物的组成部分（包括核心亚基SMARCA4）的遗传改变频率很高。然而，由SMARCA4突变驱动的肿瘤发生机制，特别是在结直肠癌（CRC）中，在很大程度上仍然未知。在这项研究中，我们在SMARCA4 （c. 3721C>T）中发现了一个特异性的热点突变，该突变导致与高级别肿瘤相关的人类CRC组织中残基1157 （R1157W）上精氨酸向色氨酸的转化，并控制CRC的进展。在机制上，我们发现SMARCA4R1157W突变促进了其招募到prmt1介导的H4R3me2a（组蛋白H4中Arg 3的不对称二甲基化），并增强了SWI/SNF复合物的atp酶活性，从而重塑CRC细胞中的染色质。我们进一步发现，SMARCA4R1157W突变体增强EGFR和TNS4的转录表达，促进CRC细胞和患者源性肿瘤类器官的增殖。重要的是，我们证明了SMARCA4R1157W CRC细胞和突变细胞衍生的异种移植物对PRMT1和SMARCA4的联合抑制更敏感，它们协同作用抑制细胞增殖。总之，我们的研究结果表明，SMARCA4-R1157W是一个关键的激活突变，通过促进染色质募集和重塑来加速结直肠癌的进展。我们的研究结果为治疗携带SMARCA4R1157W突变的结直肠癌患者提供了一种潜在的精确治疗策略。
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.
登录
查看更多内容
NatD 通过阻止组蛋白 H4 丝氨酸磷酸化激活 Slug 表达来促进肺癌进展
影响因子：
16.6
作者：
Ju J;Chen A;Deng Y;Liu M;Wang Y;Wang Y;Nie M;Wang C;Ding H;Yao B;Gui T;Li X;Xu Z;Ma C;Song Y;Kvansakul M;Zen K;Zhang CY;Luo C;Fang M;Huang DCS;Allis CD;Tan R;Zeng CK;Wei J;Zhao Q
通讯作者：
Zhao Q
哺乳动物SWI/SNF复合物的蛋白质组学和生物信息学分析确定了在人类恶性肿瘤中的广泛作用。
影响因子：
30.8
作者：
Kadoch, Cigall;Hargreaves, Diana C.;Hodges, Courtney;Elias, Laura;Ho, Lena;Ranish, Jeff;Crabtree, Gerald R.
通讯作者：
Crabtree, Gerald R.
影响因子：
5.6
作者：
Lowary, PT;Widom, J
通讯作者：
Widom, J
影响因子：
3.9
作者：
Medina, Pedro P.;Romero, Octavio A.;Sanchez-Cespedes, Montse
通讯作者：
Sanchez-Cespedes, Montse
影响因子：
64.8
作者：
KWON, H;IMBALZANO, AN;GREEN, MR
通讯作者：
GREEN, MR