STT3-mediated aberrant N-glycosylation of CD24 inhibits paclitaxel sensitivity in triple-negative breast cancer.

Abstract

Paclitaxel is one of the main chemotherapic medicines against triple-negative breast cancer (TNBC) in clinic. However, it has been perplexed by paclitaxel resistance in TNBC patients, resulting in a poor prognosis. Abnormal protein glycosylation is closely related to the occurrence and progression of tumors and malignant phenotypes such as chemotherapy resistance. CD24 is a highly glycosylated membrane protein that is highly expressed in TNBC, leading to tumorigenesis and poor prognosis. In this study we investigated the relationship between abnormal glycosylation of CD24 and paclitaxel susceptibility in TNBC and the molecular mechanisms. We showed that CD24 protein levels were significantly up-regulated in both TNBC tissues and cells, and CD24 protein was highly glycosylated. Genetic and pharmacological inhibition of N-glycosylation of CD24 enhances the anticancer activity of paclitaxel in vitro and tumor xenograft models. We revealed that the molecular mechanism of N-glycosylation of CD24 in paclitaxel resistance involved inhibition of ferroptosis, a new form that regulates cell death. Inhibition of N-glycosylation of CD24 increased glutathione consumption, iron content, and lipid peroxidation, resulting in paclitaxel-induced ferroptosis. We demonstrated that endoplasmic reticulum (ER)-associated glycosyltransferase STT3 isoforms (including both STT3A and STT3B isoforms) enable N-glycosylation of the L-asparagine (N) site. Knockout of the endogenous STT3 isoform in TNBC cells partially reduced the glycosylation status of CD24. Our results demonstrate the critical role of N-glycosylation of CD24 in weakening drug sensitivity by inhibiting ferroptosis, highlighting new insights that targeting N-glycosylation of CD24 has great potential to promote chemotherapy sensitivity and efficacy.