Saikosaponin D Mitigates Radioresistance in Triple-Negative Breast Cancer by Inducing MRE11 De-Lactylation via...

Area of Science:

• Cancer Biology
• Molecular Oncology
• Radiotherapy Research

Background:

• Triple-negative breast cancer (TNBC) is aggressive and resistant to radiotherapy, leading to poor prognosis.
• Mechanisms of TNBC radioresistance and effective therapeutic strategies are not fully understood.
• Lactate metabolism and post-translational modifications like lactylation are implicated in cancer progression.

Purpose of the Study:

• To investigate the role of lactate-driven MRE11 lactylation in TNBC radioresistance.
• To identify the delactylase responsible for MRE11 lactylation.
• To explore the radiosensitizing potential of Saikosaponin D (SSD) in TNBC.

Main Methods:

• Assessed DNA damage and repair using lactate/oxamate in irradiated TNBC cell lines.
• Utilized lentiviral vectors, Western blot, and Co-immunoprecipitation (Co-IP) to study lactylation.
• Analyzed TCGA data, tissue microarrays, proteomics, and gene expression profiling for SSD mechanisms.
• Performed promoter luciferase assays and ChIP-qPCR to map HIF1α binding sites.

Main Results:

• Elevated lactate in radioresistant TNBC promotes DNA repair via MRE11 Lys⁶⁷³ lactylation, conferring radioresistance.
• HDAC5 was identified as the key MRE11 Lys⁶⁷³ delactylase; its downregulation in TNBC was confirmed.
• Saikosaponin D (SSD) enhances radiotherapy efficacy by upregulating HDAC5, thereby inhibiting MRE11 lactylation.
• SSD activates HDAC5 expression through HIF1α binding to the HDAC5 promoter.

Conclusions:

• Lactate-driven MRE11 Lys⁶⁷³ lactylation is a key mediator of TNBC radioresistance.
• Saikosaponin D (SSD) acts as a radiosensitizer by reversing MRE11 lactylation via the HIF1α/HDAC5 axis.
• HDAC5 and MRE11 represent potential therapeutic targets for overcoming TNBC radioresistance.