N6-methyladenosine in 28S rRNA promotes oncogenic mRNA translation and tyrosine catabolism

作者：Binbin Chen, Li Li, Ying Huang, Jieyi Ma, Fei Ji, Yilin Chen, Lirong Wu, Hao Peng · 发表于：Cell Reports · 年份：2024 · DOI：10.1016/j.celrep.2024.115139 · 被引用次数：5 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、RNA Research and Splicing

Aberrant N 6 -methyladenosine (m 6 A) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of m 6 A modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated m 6 A modification on 28S rRNA are upregulated in various cancers and correlated with poor survival. Functionally, ZCCHC4 promotes intrahepatic cholangiocarcinoma (ICC) progression via its catalytic activity. Mechanistically, tether of the N 6 -adenineMIase domain of ZCCHC4 to the m 6 A site on 28S rRNA facilitates the binding of the zf-GRF-containing domain to eIF3G in the translation initiation complex and the binding of zf-DHHC-containing domain to the 3′ UTR of mRNA, therefore facilitating mRNA circularization and translation. Further analysis reveals that HPD mediates ZCCHC4's functions on tyrosine catabolism and ICC progression, and targeting HPD inhibits ICC progression in vivo . Overall, our findings uncover insights underlying mRNA translation control and provide a molecular basis for targeting the ZCCHC4-HPD axis in ICC.