FBXO11 enhances colorectal cancer progression through TMBIM6 stabilization: Echinacoside as a natural inhibitor.

BACKGROUND

FBXO11, an E3 ubiquitin ligase, has been implicated as a potential oncogenic driver in multiple cancer types; however, its biological function and therapeutic significance in colorectal cancer (CRC) remain poorly defined.

METHODS

TCGA and TNMplot databases were analyzed to assess FBXO11 expression and prognostic significance in CRC. Immunohistochemistry validated findings in 100 clinical CRC specimens. Functional impacts of FBXO11 knockdown were tested in vitro (proliferation, colony formation, migration, invasion) and in vivo. Structure-based virtual screening identified Echinacoside (ECH) as an FBXO11 inhibitor, with binding confirmed by CETSA and DARTS assays. Mechanistic studies, including in vitro pull-down and site-directed mutagenesis, interrogated FBXO11-TMBIM6 interactions and ubiquitination cascades.

RESULTS

FBXO11 was significantly upregulated in CRC tissues and correlated with poor prognosis. Its suppression inhibited CRC malignant behaviors in vitro and in vivo. ECH bound FBXO11 and triggered its ubiquitin-proteasomal degradation, suppressing CRC progression dependent on FBXO11 inhibition, reducing tumor burden in xenografts without systemic toxicity. Mechanistically, in vitro assays confirmed a direct FBXO11-TMBIM6 interaction. ECH or FBXO11 knockdown disrupted this axis, impairing K63-linked ubiquitination specifically at the K15 residue of TMBIM6, which subsequently unshielded it for K48-linked ubiquitination and proteasomal degradation of TMBIM6.

CONCLUSION

FBXO11 is a critical regulator of CRC progression via stabilization of TMBIM6 and highlights ECH as a promising therapeutic degrader targeting the FBXO11-TMBIM6 axis.