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 N⁶-methyladenosine (m⁶A) 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 m⁶A reader IGF2BP2 to stabilize m⁶A-modified DROSHA. In addition, wild-type DROSHA, but not an m⁶A methylation-deficient mutant, enhances BCSC stemness maintenance, while inhibition of DROSHA m⁶A modification attenuates BCSC traits. Our study unveils the AURKA-induced oncogenic m⁶A modification as a key regulator of DROSHA in breast cancer and identifies a novel DROSHA transcriptional function in promoting the BCSC phenotype.

RNase III DROSHA 在多种癌症中上调，并通过迄今尚不清楚的机制促进肿瘤进展。在这里，我们证明 DROSHA 与 β-Catenin 相互作用以不依赖 RNA 切割的方式反式激活STC1，从而有助于乳腺癌干细胞样细胞 (BCSC) 的特性。DROSHA mRNA 稳定性通过由 AURKA 在 BCSC 中激活的N ⁶ -甲基腺苷 (m ^{6 A) 修饰来增强。}AURKA 通过抑制 METTL14 的泛素化和降解以促进DROSHA mRNA 甲基化来稳定 METTL14。此外，AURKA 与DROSHA转录本的结合进一步加强了 m ⁶ A 阅读器 IGF2BP2 的结合以稳定 m⁶ A-修改DROSHA。此外，野生型DROSHA而非 m ⁶ A 甲基化缺陷突变体增强了 BCSC 干性维持，而DROSHA m ⁶ A 修饰的抑制减弱了 BCSC 性状。我们的研究揭示了 AURKA 诱导的致癌 m ⁶ A 修饰作为乳腺癌中DROSHA的关键调节因子，并确定了促进 BCSC 表型的新 DROSHA 转录功能。