Oncogenic AURKA-enhanced N-methyladenosine modification increases DROSHA mRNA stability to transactivate STC1 in breast cancer stem-like cells.

RNase III DROSHA is upregulated in multiple cancers and contributes to tumor progression by hitherto unclear mechanisms. Here, we demonstrate that DROSHA interacts with β-Catenin to transactivate STC1 in an RNA cleavage-independent manner, contributing to breast cancer stem-like cell (BCSC) properties. DROSHA mRNA stability is enhanced by N-methyladenosine (mA) modification which is activated by AURKA in BCSCs. AURKA stabilizes METTL14 by inhibiting its ubiquitylation and degradation to promote DROSHA mRNA methylation. Moreover, binding of AURKA to DROSHA transcript further strengthens the binding of the mA reader IGF2BP2 to stabilize mA-modified DROSHA. In addition, wild-type DROSHA, but not an mA methylation-deficient mutant, enhances BCSC stemness maintenance, while inhibition of DROSHA mA modification attenuates BCSC traits. Our study unveils the AURKA-induced oncogenic mA modification as a key regulator of DROSHA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.