CBLC inhibits ferroptosis of gastric cancer cells by inducing K48-linked polyubiquitination and degradation of SH2D4A.

BACKGROUND

Gastric cancer (GC) is a leading cause of cancer-related mortality globally, and elucidating the molecular drivers of its progression is essential for therapy development. The E3 ubiquitin ligase CBLC has been implicated in tumorigenesis, yet its role in GC remains undefined.

METHODS

CBLC expression was assessed in GC tissues and cell lines using RT-qPCR and western blot assays. The influences of CBLC on cell proliferation, migration, invasion, ferroptosis, and tumor growth were evaluated using in vitro assays, in vivo xenograft models, and rescue experiments with the ferroptosis inhibitor fer-1. Co-IP and ubiquitination assays were utilized to probe the molecular mechanisms involving CBLC.

RESULTS

CBLC level was visibly enhanced in GC tissues and cell lines. CBLC depletion curtailed GC cell proliferation, migration, and invasion in vitro and triggered ferroptosis, while also restraining tumor growth/metastasis in vivo. Fer-1 treatment reversed the tumor-suppressive effects induced by CBLC knockdown, confirming the involvement of ferroptosis. Mechanistically, CBLC promoted K48-linked polyubiquitination and proteasomal degradation of SH2D4A. Restoration of SH2D4A expression abrogated the oncogenic effects of CBLC overexpression, highlighting the CBLC/SH2D4A axis in GC progression.

CONCLUSIONS

CBLC facilitated GC progression by promoting SH2D4A degradation and suppressing ferroptosis. Targeting the CBLC/SH2D4A axis may provide a potential therapeutic strategy for GC treatment.