Kang L, Liu Y, He J, Wang Y, Xue M, Wu X, Wang Z, Zhang Y, Chu M, Li J, Wei W, Li J, Li E, Liao L, Xiao J, Zhang R, Xu L, Wong J

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest forms of human malignancy that currently lacks approved targeted therapeutics. Accumulating evidence suggests that SOX2 overexpression is a key driving factor for ESCC and various squamous cell carcinoma. Here, through screening a small-molecule kinase inhibitor library, we identified GSK3? as ...

Read More

a kinase that is critically required for robust SOX2 expression in ESCC cells. GSK3? did not promote SOX2 transcriptionally but was required for SOX2 protein stability. We demonstrated that GSK3? interacts with and phosphorylates SOX2 at residue S251, which blocks SOX2 from ubiquitination and proteasome-dependent degradation instigated by ubiquitin E3 ligase CUL4ADET1-COP1. Pharmacological inhibition or knockdown of GSK3? by RNA interference selectively impaired SOX2-positive ESCC cell proliferation, cancer stemness, and tumor growth in mouse xenograft model, suggesting that GSK3? promotes ESCC tumorigenesis primarily by driving SOX2 overexpression. GSK3? was found to be frequently overexpressed in clinical esophageal tumors, and there was a positive correlation between GSK3? and SOX2 protein levels. Notably, we found that SOX2 enhanced GSK3? expression transcriptionally, suggesting the existence of a vicious cycle that drives a coordinated GSK3? and SOX2 overexpression in ESCC cells. Finally, we demonstrated in tumor xenograft model that GSK3? inhibitor AR-A014418 was effective in suppressing SOX2-positive ESCC tumor progression and inhibited tumor progression cooperatively with chemotherapeutic agent carboplatin. In conclusion, we uncovered a novel role for GSK3? in driving SOX2 overexpression and tumorigenesis and provided evidence that targeting GSK3? may hold promise for the treatment of recalcitrant ESCCs.

Date: Jul. 01, 2023

View in: Pubmed Google Scholar

253482