IGF2BP3 Mediates the mRNA Degradation of NF1 to Promote Triple-Negative Breast Cancer Progress via an m6A-Dependent Manner

Abstract

Abstract N6-methyladenosine (m6A) is the most abundant reversible modification of eukaryotic mRNA. Emerging evidence has supported that m6A plays a vital role in tumorigenesis. As a crucial reader, IGF2BP3 usually mediates the stabilization of mRNAs in an m6A-dependent manner. However, the functions and m6A mechanism of IGF2BP3 have not been reported in triple-negative breast cancer (TNBC). Here we showed that IGF2BP3 was highly expressed in TNBC tissues and cell lines and was associated with poor prognosis. TET3-mediated IGF2BP3 promoter hypomethylation leads to upregulation of IGF2BP3 expression in TNBC. Knocking down IGF2BP3 markedly inhibited the proliferation and increased the apoptosis of TNBC in vitro and in vivo. Intersection co-assays revealed that IGF2BP3 decreased NF1 stabilization in an m6A-dependent manner. NF1 expression was negatively correlated with IGF2BP3, and knockdown of NF1 could rescue the phenotypes of IGF2BP3 knockdown cells partially in vitro and in vivo. Mechanistically, m6A reader IGF2BP3 promoted proliferation and inhibited the apoptosis of TNBC by destabilizing NF1 mRNA in an m6A-dependent manner. TET3-mediated IGF2BP3 promoter hypomethylation leads to upregulation of IGF2BP3 expression in TNBC. It suggested that IGF2BP3 has the potential to be the target for TNBC treatment.