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.