Introduction Ovarian cancer is a fatal tumor in the female, majorly associated with chemotherapy resistance. Lactylation, a novel post-translational modification, is proven to be involved in multiple biological processes. This study aims to unravel the role of histone lactylation in the development of chemoresistance in ovarian cancer.
Methods We utilized GSEA to investigate alterations in glycolysis in cisplatin sensitive/resistant patients. Differential expression of H3K9la was demonstrated using WB and IHC. Cell viability or apoptosis were measured using CCK8 or apoptosis kit, respectively. Then ChiP-seq and ChiP-qPCR were performed to identify downstream targets of H3K9la. GCN5, the potential regulator of H3K9la, was validated using protein-protein interactions and cell experiments. And IP-mass spectrometry was used to identify lactylation sites for non-histone. Lastly, we established ovarian cancer PDX models to validate the therapeutic effects of GCN5.
Results Cisplatin-resistant ovarian cancer is characterized by increased glycolysis and H3K9la expression. Inhibiting glycolysis decreased H3K9la levels and made ovarian cancer cells more sensitive to cisplatin. RAD50 were targets of H3K9la, which facilitated HR repair and conferred cisplatin resistance. Our study also found that lactylation of RAD50 enhanced HR repair. Additionally, GCN5 was identified as an upregulator of H3K9la. When combined with cisplatin, CPTH2 was effective in repressing tumor growth and burden of PDX models.
Conclusion/Implications Our study demonstrates the crucial importance of histone lactylation in regulating cisplatin response of ovarian cancer. Additionally, we identified novel potential therapy targets to overcome chemotherapy resistance, improving prognosis for patients.
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