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

Aberrant N⁶-methyladenosine (m⁶A) modification on mRNA results in dysregulated mRNA translation and cancer progression; however, the role of m⁶A modification on rRNA remains unclear in cancers. Here, we show that ZCCHC4 and its mediated m⁶A 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 N⁶-adenineMIase domain of ZCCHC4 to the m⁶A 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.