17-AAG promotes the degradation of HSP90 client METTL3 to suppress MYC RNA mA modification and expression in colorectal cancer.

Colorectal cancer (CRC) exhibits dysregulated gene expression and signaling pathways. This study explores the role of HSP90 and its client protein METTL3 in CRC progression, revealing their overexpression in CRC tissues and a positive correlation between HSP90AA1 and METTL3 expression. HSP90 interacts with METTL3's MTA70 domain via its middle substrate-binding domain, stabilizing METTL3 and enhancing its protein levels. Inhibition of HSP90 by 17-AAG reduces METTL3 stability by increasing CHIP-mediated K48-linked polyubiquitination and degradation in both nucleus and cytoplasm, decreasing mA modification on MYC mRNA and shortening its half-life without affecting METTL3 mRNA levels. RNA-seq identified 1158 genes with altered mA levels and expression post-17-AAG treatment. HSP90 inhibition suppressed CRC cell proliferation, colony formation, stemness, invasion, and migration, effects partially reversed by the METTL3-METTL14 agonist MPCH. Similar outcomes followed METTL3 inhibition with STM2457, partially rescued by MYC-stabilizing compound NNK. These findings highlight HSP90's role in stabilizing METTL3 and MYC mRNA, proposing the HSP90-METTL3 axis as a promising therapeutic target for CRC.