Related Experiment Video
Updated: Aug 22, 2026
Site-Specific Lysine Lactylation via Genetic Code Expansion in E. coli and Mammalian Cells
Published on: February 24, 2026
NID2 drives paclitaxel resistance in triple-negative breast cancer via an LDHA-lactate-histone lactylation axis
Siliang Wang1, Yitong Wang1, Kaicheng Bao1
1Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, PR China.
Abstract:
Paclitaxel resistance remains a major barrier to effective treatment of triple-negative breast cancer (TNBC). Nidogen-2 (NID2), an extracellular matrix protein, has been implicated in tumor progression, but its contribution to taxane response is unclear. Here, we integrate patient-derived evidence with mechanistic experiments to delineate the role of NID2 in paclitaxel resistance. In TNBC patient data, higher NID2 is associated with reduced paclitaxel sensitivity and increased histone lactylation signatures. In SUM149 models, NID2 silencing decreases glycolytic output, lowers extracellular lactate, and reduces global lysine lactylation, including H3K18la and H3K9la. These changes are accompanied by downregulation of key glycolysis and lactate-transport components (LDHA and MCT1) and a marked increase in paclitaxel responsiveness. In xenograft tumors, NID2 knockdown similarly suppresses glycolysis- and lactylation-related proteins and enhances the antitumor effect of paclitaxel, whereas paclitaxel alone shows limited impact on the lactylation axis. Together, our findings identify NID2 as a stromal-metabolic regulator that promotes a lactate-histone lactylation program linked to paclitaxel resistance in TNBC, and suggest NID2 as a potential target to improve taxane efficacy.
Insights
Nidogen-2 (NID2) promotes paclitaxel resistance in triple-negative breast cancer (TNBC) by increasing histone lactylation. Targeting NID2 may improve taxane treatment effectiveness for TNBC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Paclitaxel resistance is a significant challenge in treating triple-negative breast cancer (TNBC).
- Nidogen-2 (NID2), an extracellular matrix protein, is linked to tumor progression, but its role in taxane resistance is not well understood.
Purpose of the Study:
- To investigate the role of NID2 in paclitaxel resistance in TNBC.
- To explore the mechanistic link between NID2, glycolysis, histone lactylation, and taxane response.
Main Methods:
- Analysis of TNBC patient data correlating NID2 levels with paclitaxel sensitivity and histone lactylation.
- In vitro studies using SUM149 TNBC models to assess the effects of NID2 silencing on glycolysis, lactate production, and histone lactylation.
- In vivo studies using xenograft tumor models to evaluate the impact of NID2 knockdown on tumor response to paclitaxel.
Main Results:
- Higher NID2 expression in TNBC patients correlates with reduced paclitaxel sensitivity and increased histone lactylation.
- NID2 silencing in TNBC models decreased glycolysis and lactate levels, reduced histone lactylation (H3K18la, H3K9la), and enhanced paclitaxel responsiveness.
- NID2 knockdown in xenografts suppressed glycolysis and lactylation pathways, potentiating paclitaxel's antitumor effects.
Conclusions:
- NID2 acts as a stromal-metabolic regulator, driving a lactate-histone lactylation program that confers paclitaxel resistance in TNBC.
- NID2 is identified as a potential therapeutic target to overcome paclitaxel resistance and improve treatment outcomes in TNBC.
