Metastatic tumor antigen 1 contributes to hepatocarcinogenesis posttranscriptionally through RNA‐binding function

Background and Aims: Both nuclear and cytoplasmic overexpression of metastatic tumor antigen 1 (MTA1) contributes to tumorigenesis of HCC. Most studies have focused on nuclear MTA1 whose function is mainly a chromatin modifier regulating the expression of various cancer‐promoting genes. By contrast, the molecular mechanisms of cytoplasmic MTA1 in carcinogenesis remain elusive. Here, we reveal a role of MTA1 in posttranscriptional gene regulation. Approach and Results: We conducted the in vitro and in vivo RNA‐protein interaction assays indicating that MTA1 could bind directly to the 3′‐untranslated region of MYC RNA. Mutation at the first glycine of the conserved GXXG loop within a K‐homology II domain‐like structure in MTA1 (G78D) resulted in the loss of RNA‐binding activity. We used gain‐ and loss‐of‐function strategy showing that MTA1, but not the G78D mutant, extended the half‐life of MYC and protected it from the lethal ‐7–mediated degradation. The G78D mutant exhibited lower activity in promoting tumorigenesis than wild‐type in vitro and in vivo. Furthermore, RNA‐immunoprecipitation sequencing analysis demonstrated that MTA1 binds various oncogenesis‐related mRNAs besides MYC . The clinical relevance of cytoplasmic MTA1 and its interaction with MYC were investigated using HBV‐HCC cohorts with or without early recurrence. The results showed that higher cytoplasmic MTA1 level and MTA1‐ MYC interaction were associated with early recurrence. Conclusions: MTA1 is a generic RNA‐binding protein. Cytoplasmic MTA1 and its binding to MYC is associated with early recurrence in patients with HBV‐HCC. This function enables it to regulate gene expression posttranscriptionally and contributes to hepatocarcinogenesis.