FKBP9 enhances IGF2BP1-mediated m6A recognition to promote hepatocellular carcinoma progression

Background & Aims: N 6 -methyladenosine (m 6 A) modification acts on mRNA stability and translation to promote cancer progression.FK506-binding protein 9 (FKBP9), a peptidyl-prolyl isomerase, is associated with cancerigenesis, but its role in m 6 A modification remains unclear.This study aims to explore how FKBP9 regulates m 6 A modification during the development of hepatocellular carcinoma (HCC). Methods:The expression of FKBP9 in HCC was profiled by RT-qPCR, Western blot, ELISA, and immunohistochemistry, respectively.Cell proliferation, migration, invasion, apoptosis, and mRNA stability were examined using CCK-8, colony formation, flow cytometry, and cycloheximide treatment, respectively.An orthotopic allograft tumor model was constructed for in vivo analysis.Immunoprecipitation, mass spectrometry, MeRIP-seq, and RNA-seq were performed to investigate the mechanisms. ResultsFKBP9 was significantly upregulated in both patients' HCC tissues and serum (p<0.05) and correlated with unfavorable clinical outcomes (p<0.05).Its overexpression enhanced HCC cell proliferation and metastasis, while its depletion triggered cell cycle arrest and apoptosis.Mechanistically, FKBP9 interacted with the KH3-4 domains of IGF2BP1 through its PPIase domain, thereby stabilizing the binding of IGF2BP1 to m 6 A-modified MYC and PDGFB.Clinical analysis further confirmed that FKBP9 expression was positively associated with the expression of MYC and PDGFB at both the mRNA and protein levels (p<0.05).Co-overexpression of FKBP9 with MYC or J o u r n a l P r e -p r o o f PDGFB was linked to a worse prognosis (p<0.05). ConclusionsFKBP9 facilitates IGF2BP1-mediated recognition of m 6 A-modified transcripts, thus stabilizing MYC and PDGFB and accelerating HCC progression.These findings identify the FKBP9-IGF2BP1 axis as a potential therapeutic target in HCC.