SEL1L confers reduced EMT and drug resistance to breast cancer cells by promoting Shh degradation

The expression of SEL1L (suppressor/enhancer of Lin-12-like) is found to be downregulated in clinical breast cancer (BRC) and lymph node metastasis tissues, as well as in carboplatin-resistant BRC cell lines. In this study, reduced SEL1L expression was linked to poor prognosis in BRC, while silencing SEL1L in BRC cells led to increased epithelial-mesenchymal transition (EMT) and metastasis. Furthermore, SEL1L sensitized cancer cells to the anti-cancer drug carboplatin, leading to enhanced apoptosis in both <i>in vivo</i> and <i>in vitro</i> settings. Mechanistically, SEL1L suppressed the expression of oncogenic Shh protein by promoting its ubiquitination-proteasomal degradation, thereby inhibiting EMT and improving cellular sensitivity to carboplatin in BRC cells via hedgehog signaling pathway. Our findings emphasize the tumor-suppressive function of endogenous SEL1L in BRC and demonstrate the crucial role of the SEL1L-Shh-Gli1 axis in controlling cancer cell progression, offering a promising foundation for the development of innovative therapeutics against BRC.