The PIN1-YTHDF1 axis promotes breast tumorigenesis via the m6A-dependent stabilization of AURKA mRNA

The post-transcriptional processing of N 6 -methyladenosine (m 6 A)-modifi ed mRNA by YTH domain-containing familyprotein 1 (YTHDF1) plays a crucial role in the regulation of gene expression. Although YTHDF1 expression is frequentlyupregulated in breast cancer, the regulatory mechanisms for this remain unclear. In this study, we examined the role ofpeptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) in regulating YTHDF1 stability in breast cancer cells. TheWW domain of PIN1 interacted with YTHDF1 in a phosphorylation-dependent manner. Additionally, PIN1 overexpressionincreased YTHDF1 stability by preventing ubiquitin-dependent proteasomal degradation. Furthermore, using the MS2-taggedRNA pull-down assay, we identifi ed Aurora kinase A ( AURKA ) mRNA as a bona fi de substrate of YTHDF1. PIN1-mediatedYTHDF1 stabilization increased the stability of AURKA mRNA in an m 6 A-dependent manner. Furthermore, YTHDF1 knockoutreduced AURKA protein expression levels, resulting in anticancer eff ects in breast cancer cells, including decreased cellproliferation, cell cycle arrest at the G0/G1 phase, apoptotic cell death, and decreased spheroid formation. The anticancereff ects induced by YTHDF1 knockout were reversed by AURKA overexpression. Similarly, the knockout of PIN1 producedcomparable anticancer eff ects to those observed in YTHDF1-knockout cells, and these eff ects were reversed upon overexpressionof YTHDF1. In conclusion, the fi ndings of our study suggest that increased YTHDF1 stability induced by PIN1promotes breast tumorigenesis via the stabilization of AURKA mRNA. Targeting the PIN1/YTHDF1 axis may represent anovel therapeutic strategy for breast cancer.