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TGM2 Regulates Radiosensitivity via POGZ-Mediated Repair of DNA Double-Strand Breaks in Cervical Cancer
Yunbo Chi1, Peng Dong2, Ning Zhang1
1Department of Radiation Oncology, China-Japan Union Hospital of Jilin University, Changchun, China.
Abstract:
The high capacity of cancer cells for DNA damage repair constitutes a critical factor contributing to their radioresistance. Previous studies have demonstrated that aberrant expression of transglutaminase 2 (TGM2) is linked to treatment resistance. However, the role of TGM2 in cervical cancer radiosensitivity and its underlying mechanisms remain unclear. In this study, we found that TGM2 was significantly upregulated in radioresistant cervical cancer cells and tissues. TGM2 knockdown significantly enhanced the radiosensitivity of cervical cancer cells, while TGM2 overexpression conferred radioresistance. TGM2 depletion exacerbated ionizing radiation (IR)-induced DNA double-strand breaks (DSBs). Mechanistically, IR triggered the nuclear translocation of TGM2, where it physically interacted with POGO transposable element derived with ZNF domain protein (POGZ) and upregulated POGZ protein levels. TGM2 knockdown impaired BRCA1 recruitment to DSB sites, phenocopying POGZ depletion effects. Rescue experiments demonstrated that POGZ knockdown reversed the radioresistance and reduction in DNA DSBs caused by TGM2 overexpression. Subcutaneous xenograft mouse models further verified these findings and the regulatory role of TGM2 in cervical cancer radiosensitivity in vivo. Together, our results demonstrated that TGM2 regulates radiosensitivity by POGZ-mediated DNA DSBs repair, providing a novel strategy for increasing cervical cancer radiosensitivity.
Insights
Transglutaminase 2 (TGM2) promotes radioresistance in cervical cancer by enhancing DNA repair. Targeting TGM2 and its interaction with POGO transposable element derived with ZNF domain protein (POGZ) may improve cancer treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Cancer cell radioresistance is a major challenge in treatment, often linked to DNA repair mechanisms.
- Aberrant expression of transglutaminase 2 (TGM2) is associated with treatment resistance, but its role in cervical cancer radiosensitivity is unknown.
Purpose of the Study:
- To investigate the role of TGM2 in cervical cancer radiosensitivity and elucidate its underlying molecular mechanisms.
Main Methods:
- Quantitative analysis of TGM2 expression in radioresistant cervical cancer cells and tissues.
- In vitro studies involving TGM2 knockdown and overexpression to assess radiosensitivity.
- Investigation of TGM2's interaction with POGO transposable element derived with ZNF domain protein (POGZ) and BRCA1 recruitment to DNA double-strand breaks (DSBs) after ionizing radiation (IR).
- In vivo validation using subcutaneous xenograft mouse models.
Main Results:
- TGM2 was significantly upregulated in radioresistant cervical cancer cells and tissues.
- TGM2 knockdown enhanced radiosensitivity, while overexpression conferred resistance.
- TGM2 depletion increased IR-induced DNA DSBs and impaired BRCA1 recruitment, similar to POGZ depletion.
- POGZ knockdown reversed the effects of TGM2 overexpression on radioresistance and DSB repair.
- In vivo studies confirmed TGM2's role in regulating cervical cancer radiosensitivity.
Conclusions:
- TGM2 promotes cervical cancer radioresistance by enhancing POGZ-mediated DNA DSB repair.
- TGM2 represents a potential therapeutic target for overcoming radioresistance in cervical cancer.
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