Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, 430030, China.
Cell Death Dis. 2022 Nov 5;13(11):926. doi: 10.1038/s41419-022-05386-4.
As the most important RNA epigenetic regulation in eukaryotic cells, N6-metheyladenosine (mA) modification has been demonstrated to play significant roles in cancer progression. However, this modification in long intergenic non-coding RNAs (lincRNAs) and the corresponding functions remain elusive. Here, we showed a lincRNA LINC02551 was downregulated by AlkB Homolog 5 (ALKBH5) overexpression in a mA-dependent manner in hepatocellular carcinoma (HCC). Functionally, LINC02551 was required for the growth and metastasis of HCC. Mechanistically, LINC02551, a bona fide mA target of ALKBH5, acted as a molecular adaptor that blocked the combination between DDX24 and a E3 ligase TRIM27 to decrease the ubiquitination and subsequent degradation of DDX24, ultimately facilitating HCC growth and metastasis. Thus, ALKBH5-mediated LINC02551 mA methylation was required for HCC growth and metastasis.
作为真核细胞中最重要的 RNA 表观遗传调控之一，N6-甲基腺苷（m6A）修饰已被证明在癌症进展中发挥重要作用。然而，这种修饰在长非编码 RNA（lncRNA）中的作用及其相应功能仍不清楚。在这里，我们发现 ALKBH5 过表达以 m6A 依赖的方式下调肝癌（HCC）中的 lincRNA LINC02551。功能上，LINC02551 是 HCC 生长和转移所必需的。在机制上，LINC02551 是 ALKBH5 的真正 m6A 靶标，作为分子衔接物，阻止了 DDX24 与 E3 连接酶 TRIM27 的结合，从而减少了 DDX24 的泛素化和随后的降解，最终促进了 HCC 的生长和转移。因此，ALKBH5 介导的 LINC02551 m6A 甲基化对于 HCC 的生长和转移是必需的。
