PIPKIγ promotes non-homologous end joining through LIG4 to enhance radiotherapy resistance in triple-negative breast cancer
Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and limited therapeutic options. DNA damage-based radiotherapy plays a significant role in the treatment of TNBC. However, radioresistance continues to pose a significant challenge, often resu...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07894-5 |
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| Summary: | Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis and limited therapeutic options. DNA damage-based radiotherapy plays a significant role in the treatment of TNBC. However, radioresistance continues to pose a significant challenge, often resulting in the unsuccessful outcome of radiation therapy for patients with TNBC. Type I gamma phosphatidylinositol phosphate kinase (PIPKIγ), a key enzyme in phosphoinositide metabolism, is associated with poor prognostic outcomes in TNBC. Here, we discovered that PIPKIγ overexpression significantly boosts nonhomologous end joining (NHEJ), a principal mechanism for repairing DNA double-strand breaks (DSBs). This enhancement of NHEJ confers increased radioresistance in TNBC. At the molecular level, PIPKIγ directly interacts with LIG4, a crucial NHEJ component, and strengthens its interaction with XRCC4, a key regulator of LIG4 nuclear translocation. This facilitates LIG4’s nuclear translocation, improving DNA repair efficiency and genomic stability in TNBC cells. Furthermore, elevated PIPKIγ levels enhance radioresistance in TNBC cells and tumors in xenograft models, whereas depleting PIPKIγ has the opposite effects. These insights reveal a new mechanism by which PIPKIγ promotes radioresistance through the facilitation of DSBs repair in TNBC. Collectively, our findings suggest that the PIPKIγ-LIG4 interaction represents a potential therapeutic target for improving radiotherapy efficacy in TNBC patients. |
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| ISSN: | 2041-4889 |