PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer
PRMT5 regulates RNA m6A demethylation for doxorubicin sensitivity in breast cancer
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PRMT5 调节 RNA m6A 去甲基化以提高乳腺癌中阿霉素的敏感性
DOI：
10.1016/j.ymthe.2022.03.003
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发表时间：
2022-07-06
影响因子：
12.4
通讯作者：
Zhang, Jian
中科院分区：
文献类型：
--
作者：
Wu, Ying;Wang, Zhe;Zhang, Jian
癌细胞通过RNAm6A修饰的动态调节对各种应激条件做出反应。多柔比星是一种广泛使用的化疗药物，可导致DNA损伤。了解癌细胞是否通过RNAm6A修饰来调节DNA损伤反应和阿霉素敏感性是一件有趣的事情。在这里，我们发现阿柔比星治疗以剂量和时间依赖的方式显著诱导乳腺癌细胞中RNAm6A甲基化。然而，蛋白精氨酸甲基转移酶5(PRMT5)通过促进RNA去甲基酶AlkB同源5(ALKBH5)的核易位而抑制了阿霉素处理下的RNA m6A修饰，此前人们认为ALKBH5仅定位于细胞核。然后，ALKBH5消除了BRCA1的m6A甲基化以稳定mRNA，并进一步增强了DNA修复能力，从而降低了乳腺癌细胞中阿霉素的疗效。重要的是，我们确定批准的药物他达拉非是一种新型的PRMT5抑制剂，可以减少RNAm6A甲基化，并增加乳腺癌对阿霉素的敏感性。靶向PRMT5和他达拉非的策略是通过RNA甲基化调节提高乳腺癌对阿霉素敏感性的一种有前景的方法。
Cancer cells respond to various stressful conditions through the dynamic regulation of RNA m6A modification. Doxoru-bicin is a widely used chemotherapeutic drug that induces DNA damage. It is interesting to know whether cancer cells regulate the DNA damage response and doxorubicin sensitivity through RNA m6A modification. Here, we found that doxoru-bicin treatment significantly induced RNA m6A methylation in breast cancer cells in both a dose-and a time-dependent manner. However, protein arginine methyltransferase 5 (PRMT5) inhibited RNA m6A modification under doxorubicin treatment by enhancing the nuclear translocation of the RNA demethylase AlkB homolog 5 (ALKBH5), which was previously believed to be exclusively localized in the nucleus. Then, ALKBH5 removed the m6A methylation of BRCA1 for mRNA stabilization and further enhanced DNA repair compe-tency to decrease doxorubicin efficacy in breast cancer cells. Importantly, we identified the approved drug tadalafil as a novel PRMT5 inhibitor that could decrease RNA m6A methyl-ation and increase doxorubicin sensitivity in breast cancer. The strategy of targeting PRMT5 with tadalafil is a promising approach to promote breast cancer sensitivity to doxorubicin through RNA methylation regulation.