PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling.
PRMT1-mediated H4R3me2a recruits SMARCA4 to promote colorectal cancer progression by enhancing EGFR signaling.
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PRMT1 介导的 H4R3me2a 招募 SMARCA4，通过增强 EGFR 信号传导来促进结直肠癌进展。
DOI：
10.1186/s13073-021-00871-5
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发表时间：
2021-04-14
期刊：
影响因子：
12.3
通讯作者：
Zhao Q
中科院分区：
文献类型：
--
作者：
Yao B;Gui T;Zeng X;Deng Y;Wang Z;Wang Y;Yang D;Li Q;Xu P;Hu R;Li X;Chen B;Wang J;Zen K;Li H;Davis MJ;Herold MJ;Pan HF;Jiang ZW;Huang DCS;Liu M;Ju J;Zhao Q
表观遗传机制的异常变化如组蛋白修饰在癌症进展中起重要作用。PRMT 1触发组蛋白H4在精氨酸3上的不对称二甲基化（H4 R3 me 2a），在人类结直肠癌（CRC）中上调，并且对于细胞增殖至关重要。然而，这种失调的修饰如何导致CRC的恶性转化仍然知之甚少。在这项研究中，我们整合了包括蛋白质相互作用研究和染色质免疫沉淀（ChIP）在内的生化分析，包括细胞活力，增殖，集落形成和迁移分析在内的细胞分析，临床样本分析，微阵列实验和ChIP-Seq数据，以研究CRC细胞中H4 R3 me 2s的潜在基因组识别模式及其对CRC进展的影响。我们发现PRMT 1和SMARCA 4，SWI/SNF染色质重塑复合物的ATP酶亚基，合作促进结直肠癌（CRC）进展。我们发现SMARCA 4是PRMT 1介导的H4 R3 me 2a的一种新的效应分子。从机制上讲，我们表明H4 R3 me 2a直接招募SMARCA 4，通过增强EGFR信号传导促进CRC细胞的增殖，集落形成和迁移能力。我们发现EGFR和TNS 4是结肠细胞中PRMT 1和SMARCA 4的主要直接下游转录靶点，并以PRMT 1甲基转移酶活性依赖性方式促进CRC细胞增殖。在体内，PRMT 1的敲低或抑制显著减弱了C57 BL/6 J-ApcMin/+ CRC小鼠模型中CRC细胞的生长。重要的是，CRC患者中PRMT 1或SMARCA 4的表达升高与EGFR和TNS 4的表达呈正相关，CRC患者的总生存期较短。这些发现揭示了CRC进展过程中表观遗传和转录控制之间的关键相互作用，表明SMARCA 4是CRC的一种新的关键表观遗传调节剂。因此，我们的研究结果强调PRMT 1/SMARCA 4抑制作为CRC的潜在治疗干预策略。PRMT 1介导的H4 R3 me 2a招募SMARCA 4，SMARCA 4通过增强EGFR信号传导促进结直肠癌进展。在线版本包含补充材料，可通过10.1186/s13073-021-00871-5获得。
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. 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. 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. PRMT1-mediated H4R3me2a recruits SMARCA4, which promotes colorectal cancer progression by enhancing EGFR signaling. The online version contains supplementary material available at 10.1186/s13073-021-00871-5.
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影响因子：
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