NUP62 Elevates USP10 Expression and Promotes Tamoxifen Resistance of Breast Cancer by Deubiquitinating ERα.

Abstract

Breast cancer (BRCA) continues to be a major global health challenge around the world. Overcoming endocrine resistance remains one of the most significant challenges in the global fight against the disease. This study investigates the function of nucleoporin 62 (NUP62) in BRCA progression and evaluates its potential as a therapeutic target. Analysis of clinical breast tumor specimens and ERα-positive cell lines revealed that NUP62 expression was significantly upregulated in BRCA, especially in ERα-positive subtypes. In ERα-positive BRCA, high NUP62 levels were strongly linked to inferior survival and served as a robust indicator of adverse prognosis. Through in vitro functional assays, NUP62 was shown to facilitate proliferation, invasion, migration, and the epithelial-mesenchymal transition (EMT) in ERα-positive BRCA cells. Mechanistic studies identified that NUP62 promotes deubiquitinase USP10 transcription. Subsequently, USP10 binds to ERα, resulting in enhanced ERα protein stability and the activation of downstream oncogenic signaling. Notably, NUP62 depletion restored tamoxifen sensitivity in endocrine-resistant BRCA cells by compromising ERα stability. This work establishes NUP62 as a prognostic marker, revealing its dual function in promoting ERα-positive tumorigenesis and conferring endocrine resistance. These findings suggest that therapeutic targeting of NUP62 could be a viable strategy to enhance tamoxifen response and combat resistance in ERα-positive breast cancer.