Integrative Proteomics and Histone PTMomics Study on Anti-TNBC Effect of JIB-04
Shengna Tao1,2, Jingli Guo2,3, Jingdan Zhang4,5
1Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang 222005, China.
Abstract:
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.
Insights
JIB-04, an epigenetic inhibitor, shows promise against triple-negative breast cancer (TNBC) by impacting DNA damage response, cell cycle arrest, and apoptosis. This study reveals its molecular mechanisms, offering new therapeutic options for TNBC.
Area of Science:
- Oncology
- Epigenetics
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to its aggressive nature and limited treatment options.
- Epigenetic modifications, particularly histone marks, play a crucial role in cancer development and progression.
- Histone lysine demethylases (KDMs) are emerging therapeutic targets for TNBC, with JIB-04 showing preclinical anticancer activity.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying the antitumor effects of the KDM inhibitor JIB-04 in TNBC.
- To comprehensively characterize changes in histone post-translational modifications (PTMs) and protein expression profiles following JIB-04 treatment.
- To identify key signaling pathways modulated by JIB-04 in TNBC cells.
Main Methods:
- Integrated analysis of histone PTMomics and quantitative proteomics.
- Identification and quantification of differentially expressed histone PTM sites and proteins.
- Pathway enrichment analysis to determine affected signaling cascades.
Main Results:
- JIB-04 treatment altered 14 histone PTM sites, including newly identified H3K79me2 and H3K9ac.
- Quantitative proteomics revealed 904 differentially expressed proteins (495 upregulated, 409 downregulated).
- Pathway analysis indicated significant modulation of the DNA damage response (DDR) by JIB-04.
Conclusions:
- JIB-04 effectively modulates the DNA damage response, induces cell cycle arrest, and promotes apoptosis in TNBC.
- This study provides novel mechanistic insights into JIB-04's anticancer activity.
- JIB-04 represents a promising therapeutic candidate for TNBC treatment.
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