Metastatic tumor antigen 1 contributes to hepatocarcinogenesis posttranscriptionally through RNA-binding function.
Hepatology
; 77(2): 379-394, 2023 02 01.
Article
en En
| MEDLINE
| ID: mdl-35073601
ABSTRACT
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 ANDRESULTS:
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Carcinoma Hepatocelular
/
Neoplasias Hepáticas
Límite:
Humans
Idioma:
En
Revista:
Hepatology
Año:
2023
Tipo del documento:
Article
País de afiliación:
Taiwán