JAC1 Targets YY1-Mediated JWA/p38 MAPK Signaling To Inhibit Proliferation and Induce Apoptosis In TNBC
Abstract Background: Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and still has no adequate therapeutic target and ideal medicine. The public database and the relative studies have shown that low expression of JWA is closely related to the poor overall survival in many cancers including breast cancer. However, the precise biological functions and behind mechanisms of JWA in TNBC are still unclear.Methods: Both TCGA and GEO databases were used to confirm the relationship between expression levels of JWA and overall survival in TNBC cases. JAC1, an agonistic small compound of JWA gene, was used in TNBC models in vitro and in vivo. The routine cellular and molecular assays include CCK-8, colony formation, EdU incorporation, the flow cytometry, Western blot, immunohistochemistry, immune-fluorescence microscopy and reporter gene assays were conducted in this study.Results: Low expression of JWA was associated with poor prognosis in TNBC patients. JAC1 treatment inhibited TNBC cells proliferation and promoted apoptosis in vitro and in vivo. JAC1 specifically combined and targeted YY1 to eliminate its transcriptional inhibition on JWA gene. At the same time, JAC1 promoted ubiquitination and degradation of YY1. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway.Conclusions: We discovered for the first time that JAC1 is a YY1 targeting compound and maybe a potential therapeutic agent for TNBC.