PRMT5-Mediated ALKBH5 Methylation Promotes Colorectal Cancer Immune Evasion via Increasing CD276 Expression.

IF 11 1区 综合性期刊 Q1 Multidisciplinary
Research Pub Date : 2025-01-08 eCollection Date: 2025-01-01 DOI:10.34133/research.0549
Sen Meng, Hao Liu, Jiayu Xu, Chuyin Deng, Xingyou Qian, Sufang Chu, Wei-Guo Zhu, Jiuling Zhu, Hongmei Yong, Zhongwei Li, Jin Bai
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引用次数: 0

Abstract

Numerous diseases have been connected to protein arginine methylations mediated by protein arginine methyltransferase 5 (PRMT5). Clinical investigations of the PRMT5-specific inhibitor GSK3326595 are currently being conducted, and the results are promising for preventing cancers. However, the detailed mechanism of PRMT5 promoting colorectal cancer (CRC) malignant progression remains unclear. Here, we found that PRMT5 directly catalyzes AlkB homologue 5 (ALKBH5) symmetric dimethylation at the R316 residue (meR316-ALKBH5), which enhances TRIM28-mediated ALKBH5 ubiquitination degradation. Then, an ALKBH5 decrease attenuates ALKBH5-mediated m6A demethylation on the CD276 transcript 3' untranslated region, which increases CD276 messenger RNA stability and its expression in CRC cells. Furthermore, a CD276 expression increase facilitates CRC immune evasion by inhibiting cytotoxic T-cell functions. Moreover, we revealed that PRMT5-mediated meR316-ALKBH5 activates CD276 transcription by increasing its messenger RNA m6A modification to increase CRC immune evasion in vitro and in vivo. Furthermore, we consistently showed a strong association between meR316-ALKBH5 and poor outcomes in patients with CRC. Finally, we demonstrated that combining an anti-PD1 antibody with the PRMT5 inhibitor GSK3326595 markedly halts the progression of CRC. Our findings could serve as a basis for the development of a PRMT5-meR316-ALKBH5-CD276 axis-targeting treatment approach for CRC.

prmt5介导的ALKBH5甲基化通过增加CD276表达促进结直肠癌免疫逃避。
许多疾病都与蛋白精氨酸甲基转移酶5 (PRMT5)介导的蛋白精氨酸甲基化有关。prmt5特异性抑制剂GSK3326595的临床研究目前正在进行中,其结果有望用于预防癌症。然而,PRMT5促进结直肠癌(CRC)恶性进展的详细机制尚不清楚。本研究发现,PRMT5直接催化了AlkB同源物5 (ALKBH5)在R316残基(meR316-ALKBH5)上的对称二甲基化,增强了trim28介导的ALKBH5泛素化降解。然后,ALKBH5的减少减弱了ALKBH5介导的CD276转录本3'非翻译区m6A去甲基化,从而增加了CD276信使RNA的稳定性及其在CRC细胞中的表达。此外,CD276表达增加通过抑制细胞毒性t细胞功能促进结直肠癌免疫逃避。此外,我们发现prmt5介导的meR316-ALKBH5通过增加其信使RNA m6A修饰来激活CD276转录,从而在体外和体内增加CRC免疫逃避。此外,我们一致显示meR316-ALKBH5与结直肠癌患者的不良预后之间存在强烈关联。最后,我们证明了将抗pd1抗体与PRMT5抑制剂GSK3326595结合可以显著阻止CRC的进展。我们的研究结果可以作为开发PRMT5-meR316-ALKBH5-CD276轴靶向治疗结直肠癌方法的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Research
Research Multidisciplinary-Multidisciplinary
CiteScore
13.40
自引率
3.60%
发文量
0
审稿时长
14 weeks
期刊介绍: Research serves as a global platform for academic exchange, collaboration, and technological advancements. This journal welcomes high-quality research contributions from any domain, with open arms to authors from around the globe. Comprising fundamental research in the life and physical sciences, Research also highlights significant findings and issues in engineering and applied science. The journal proudly features original research articles, reviews, perspectives, and editorials, fostering a diverse and dynamic scholarly environment.
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