Li Jing, Zhang Xinxin, Zhao Si-Yi, Ran Ling, Zhang Minmin, Xie Shan, Zhu Huifang, Yan Guang-Rong
Biomedicine Research Center, Guangdong Provincial Key Laboratory of Major Obstetric Disease, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
Oncogene. 2025 Jun 19. doi: 10.1038/s41388-025-03473-2.
N-Methyladenosine (mA) is the most abundant modification in mRNAs and regulates RNA splicing, stabilization, translation and export. FTO was the first discovered RNA mA demethylase, and it is frequently dysregulated in cancers and plays important roles in tumorigenesis, cancer cell stemness, immune evasion, metabolic programs and drug resistance. Here, we report that FTO is acetylated at lysine 88 (K88) by the acetyltransferase GCN5 in vivo and in vitro. K88 acetylation significantly increases the RNA mA demethylase activity of FTO. Acetylation of FTO at K88 has no effect on its stability, localization or dimerization but significantly increases its binding to mA-modified RNA, thereby facilitating the removal of mA from RNA. K88 acetylation is markedly increased in cancers, and the elimination of K88 acetylation in FTO inhibits the ability of FTO to stimulate tumorigenesis. K88 acetylation facilitates a reduction in the mA level of FTO target mRNAs MYC, PDGFC, SOX10, CXCR4, NRF2, PLD1 and CDC42 and subsequently alters the stability or translation of these target mRNAs, thereby promoting tumorigenesis. Hence, K88 acetylation is critical for the RNA mA demethylase activity and tumor-promoting functions of FTO.
N-甲基腺苷（mA）是mRNA中最丰富的修饰，可调节RNA剪接、稳定性、翻译和输出。FTO是首个被发现的RNA mA去甲基化酶，它在癌症中经常失调，在肿瘤发生、癌细胞干性、免疫逃逸、代谢程序和耐药性中发挥重要作用。在此，我们报告FTO在体内和体外被乙酰转移酶GCN5在赖氨酸88（K88）处乙酰化。K88乙酰化显著增加FTO的RNA mA去甲基化酶活性。FTO在K88处的乙酰化对其稳定性、定位或二聚化没有影响，但显著增加其与mA修饰的RNA的结合，从而促进从RNA上去除mA。K88乙酰化在癌症中显著增加，FTO中K88乙酰化的消除抑制了FTO刺激肿瘤发生的能力。K88乙酰化促进FTO靶标mRNA MYC、PDGFC、SOX10、CXCR4、NRF2、PLD1和CDC42的mA水平降低，随后改变这些靶标mRNA的稳定性或翻译，从而促进肿瘤发生。因此，K88乙酰化对于FTO的RNA mA去甲基化酶活性和促肿瘤功能至关重要。
