YTHDF3 Facilitates eIF2AK2 and eIF3A Recruitment on mRNAs to Regulate Translational Processes in Oxaliplatin-Resistant Colorectal Cancer

Oxaliplatin, as a first-line drug,
frequently causes chemo-resistance
in colorectal cancer (CRC). The role of N6-methyladenosine (m6A) modification
in multiple biological functions has been well studied. However, the
molecular mechanisms underlying m6A methylation in modulating anti-cancer
drug resistance in CRC remain obscure. In the present study, we found
that YTH m6A RNA-binding protein 3 (YTHDF3) was highly expressed in
oxaliplatin-resistant (OXAR) CRC tissues and cells. Moreover, we observed
that YTHDF3 could recognize the 5′ untranslated region of significantly
m6A-methylated RNAs, which were associated with tumor resistance and
recruit eukaryotic translation initiation factor 3 subunit A (eIF3A)
to facilitate the translation of these target genes. Furthermore,
we determined that eukaryotic translation initiation factor 2 alpha
kinase 2 (eIF2AK2) bridged YTHDF3 and eIF3A, enhancing the stability
of the YTHDF3/eIF3A complex in OXAR CRC cells. Taken together, our
data identified YTHDF3 as a novel hallmark and revealed the molecular
mechanism of YTHDF3 on gene translation via coordination
with eIF2AK2 in OXAR CRC cells.