Zhang Haisheng, Lu Linlin, Yi Cheng, Jiang Tao, Lu Yunqing, Yang Xianyuan, Zhong Ke, Zhou Jiawang, Li Jiexin, Xie Guoyou, Chen Zhuojia, Jiang Zongpei, Asadikaram Gholamreza, Peng Yanxi, Zhou Dan, Wang Hongsheng
Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery; State Key Laboratory of Anti-Infective Drug Discovery and Development; School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
Institute of Medical Sciences, the Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250033, China.
Acta Pharm Sin B. 2025 Mar;15(3):1552-1570. doi: 10.1016/j.apsb.2024.12.037. Epub 2025 Jan 3.
The interaction between mA-methylated RNA and chromatin modification remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or its inhibitor (JQ1) significantly decreases mRNA mA levels and suppresses the malignancy of breast cancer (BC) cells increased expression of demethylase AlkB homolog 5 (ALKBH5). Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 enhanced binding between its 3' untranslated regions (3'UTRs) with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes tripartite motif containing-21 (TRIM21) and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of extra spindle pole bodies like 1 (ESPL1) and reduces binding between mRNA and mA reader insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leading to decay of mRNA. Animal and clinical studies confirm a critical role of BRD4/ALKBH5/ESPL1 pathway in BC progression. Further, our study sheds light on the crosstalks between histone modification and RNA methylation.
N⁶-甲基化RNA与染色质修饰之间的相互作用在很大程度上仍不清楚。我们发现，通过小干扰RNA（siRNA）或其抑制剂（JQ1）靶向抑制含溴结构域蛋白4（BRD4）可显著降低mRNA的m⁶A水平，并抑制乳腺癌（BC）细胞的恶性程度，这与去甲基化酶AlkB同源物5（ALKBH5）表达增加有关。从机制上讲，抑制BRD4可增加ALKBH5的mRNA稳定性，这是通过增强其3'非翻译区（3'UTR）与RNA结合蛋白RALY之间的结合来实现的。此外，BRD4作为泛素酶含三联体基序蛋白21（TRIM21）和ALKBH5的支架，导致ALKBH5蛋白的泛素化和降解。JQ1增加的ALKBH5随后使额外纺锤极体样蛋白1（ESPL1）的mRNA去甲基化，并减少mRNA与m⁶A阅读蛋白胰岛素样生长因子2 mRNA结合蛋白3（IGF2BP3）之间的结合，导致mRNA降解。动物和临床研究证实了BRD4/ALKBH5/ESPL1通路在BC进展中的关键作用。此外，我们的研究揭示了组蛋白修饰与RNA甲基化之间的相互作用。
