SPOP/NOLC1/B4GALT1 signaling axis enhances paclitaxel resistance in endometrial cancer by inducing O-dysglycosylation.

Abstract

The effective treatment of paclitaxel-resistant patients remains a major challenge. We found that nucleolar and coiled body phosphoprotein 1 (NOLC1) was highly expressed in the paclitaxel-resistant endometrial cancer (ECa) cells and pathological tissue of ECa patients, which could promote the occurrence and progression of ECa cells. Mechanistically, we confirmed that the E3 ubiquitin ligase substrate-binding adaptor SPOP mediates the ubiquitination and degradation of NOLC1, thereby maintaining normal protein levels. However, ECa-associated SPOP mutants abrogated the binding and ubiquitination of NOLC1, resulting in the accumulation of NOLC1, and ultimately promoting the proliferation, migration, and invasion of ECa cells. In addition, we demonstrated that NOLC1 could act as a transcriptional factor to activate the transcriptional expression of B4GALT1, ultimately leading to abnormal glycosylation metabolism. Moreover, knockdown of B4GALT1 can partly counteract the cancer-promoting effect caused by the overexpression of NOLC1 in vitro and in vivo. Based on these findings, an O-glycosylation inhibitor combined with paclitaxel could effectively improve the sensitivity of paclitaxel-resistant cells. In summary, we found that SPOP can negatively regulate the NOLC1-B4GALT1 signaling axis in ECa, whereas ECa-associated SPOP mutants lead to abnormal activation of this signaling axis, leading to glycosylation metabolism disorders. In addition, paclitaxel combined with B4GALT1-KD or glycosylation inhibitors can significantly inhibit the growth of paclitaxel-resistant endometrial cancer cells.