YAP Expression Confers Therapeutic Vulnerability to Cuproptosis in Breast Cancer Cells by Regulating Copper Homeostasis

Abstract

Copper metabolism plays a complex role in tumor growth and cancerprogression and thus holds potential as a therapeutic target. However,reliable diagnostic markers and therapeutic tools for successfully predictingpersonalized treatment outcomes with copper inhibition remain elusive. Inthis study, it is discovered that Yes-associated protein (YAP) expressionconferred susceptibility toward cuproptosis. Molecular analyses revealed thatYAP inhibition significantly abolished cuproptotic characteristics.Interestingly, YAP inhibition does not affect protein lipoylation but disruptscopper homeostasis. Mechanistically, YAP regulates antioxidant-1 (ATOX1), acopper chaperone, and overexpression of ATOX1 restored cuproptoticsensitivity in YAP-silenced cells. To advance copper-targeting therapy, it isidentified that melatonin inhibited YAP signaling and attenuated theexpression of copper metabolism-related genes. Furthermore, a copper-basedfunctional nanomaterial, EsMP@Fu is developed, which incorporatesmelatonin and the cuproptosis inducer elesclomol complex with copper ions(Cu(II)) (Es:Cu). This formulation facilitates cuproptotic cytotoxicity viafucoidan-decorated nanocarrier to enhance the targeted delivery toward tumorcells. In vivo study demonstrated that EsMP@Fu significantly suppressedtumor growth by 60%, with more pronounced effects on distant metastasisand the induction of antitumor immunity. Collectively, the findingsdemonstrate that YAP overexpression confers sensitivity and therapeuticvulnerability to cuproptosis induction, presenting a promising strategy forprecision medicine through tailored copper-based therapy.