TRIM21 promotes K63-linked ubiquitination of ALKBH5 and suppresses cuproptosis via down-regulation of LIAS in esophageal squamous cell carcinoma.

Cuproptosis is a newly discovered programmed cell death regulated by lipoic acid synthase (LIAS) in cancer cells. However, its functions in Esophageal squamous cell carcinoma (ESCC) and the underlying mechanism remains unclear. Here, we show that in human ESCC cells, TRIM21 facilitates the K63-linked ubiquitination dependent translocation of ALKBH5 from cytosol to nucleus and augments its m6A demethylase activity. LIAS mRNA was demethylated by ALKBH5, and then further identified by reader IGF2BP3, which comprehensively caused the lower expression of LIAS. Moreover, O-GlcNAc transferase OGT facilitated TRIM21-mediated K63-ubiquitination of ALKBH5. Combined treatment with an OGT inhibitor OSMI-1 and copper ionophore elesclomol eliminates tumor growth and remarkably enhances the sensitivity of tumor cells to cisplatin. Together, our study identifies TRIM21 Ubiquitinated-ALKBH5 as a critical gatekeeper to restrict cuproptosis, and such mechanism may contribute to tumor development and drug resistance in ESCC.