Integrative Proteomics and Histone PTMomics Study on Anti-TNBC Effect of JIB-04.

The incidence of malignant breast cancer is increasing, and triple-negative breast cancer (TNBC) is particularly challenging due to its poor prognosis and limited response to conventional treatments. Recently, epigenetic inhibitors have emerged as promising therapeutic strategies for TNBC. JIB-04, that targeted histone lysine demethylases (KDMs), was reported to show anticancer activities against TNBC. However, the molecular mechanism underlying the antitumor effect of JIB-04 remains elusive. Herein, we integrated histone PTMomics and quantitative proteomics to comprehensively characterize histone PTM site changes and signaling pathway alterations. Under JIB-04 treatment, a total of 14 significantly altered histone PTM sites were identified, including previously reported sites (H3K9me2, H3K9me3, and H3K36me3) and two newly reported sites (H3K79me2 and H3K9ac). Proteomic analysis quantified 904 differentially expressed proteins, including 495 upregulated and 409 downregulated proteins. Pathway enrichment analysis suggested that JIB-04 significantly affected the DNA damage response. Further biological evidence demonstrated that JIB-04 modulated DNA damage response, cell cycle arrest, and apoptosis. In summary, our study provides new mechanistic insights into the anticancer activity of JIB-04 and offers new options for the treatment of TNBC.