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Defining the role of Tip60 in the DNA damage response of glioma cell lines
K Bannik1, A Sak1, M Groneberg1
1Department of Radiotherapy, University Hospital Essen, Essen, Germany.
Purpose:
Glioblastomas are resistant to conventional therapies, including radiotherapy. Our previous study proved that epigenetic regulation influences the radiation response of glioma cells. This study evaluated the role of the acetyltransferase Tip60 on the radiation response.
Material And Methods:
Tip60 expression was down-regulated by transfecting specific siRNA's in A7 and MO59K cells with high and low expression of Tip60, respectively, and its effect on survival was assessed. DNA repair was analyzed by foci scoring (γH2AX, Rad51, 53BP1, pATM). The interaction of Tip60 with ATM and DNA-PK was investigated using the specific inhibitors KU55933 and NU7441, respectively.
Results:
Knockdown of Tip60 significantly (p < .001) reduced survival in both cell lines, but the effect was more pronounced in A7 cells. ATMi and DNA-PKi significantly reduced the surviving fraction following irradiation. However, no further effect of siTip60 on the radiosensitivity of ATMi treated A7 cells was observed. In contrast, DNA-PKi effectively enhanced the sensitizing effect of siTip60. Mechanistically, siTip60 reduced the number of initial Rad51 and ATM foci formation after irradiation and prevented their dissolution at 24 h. siTip60 had no impact on the formation of 53BP1 and γH2AX foci and did not further affect these end-points if combined with ATMi or DNA-PKi.
Conclusions:
Downregulation of Tip60 enhances the radiation sensitivity of both glioma cells and markedly elevates the radiation sensitivity when combined with DNA-PKi. Therefore, treatment with DNA-PK inhibitors represents a promising approach to augment the radiation sensitivity of glioma cell lines with deficient Tip60 activity in a synergistic manner.
Insights
Downregulating the acetyltransferase Tip60 increases glioma cell sensitivity to radiation. Combining Tip60 inhibition with DNA-PK inhibitors synergistically enhances radiosensitivity, offering a promising therapeutic strategy for glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Glioblastomas exhibit resistance to conventional therapies like radiotherapy.
- Epigenetic regulation plays a role in glioma cell radiation response.
Purpose of the Study:
- To evaluate the role of the acetyltransferase Tip60 in glioblastoma radiation response.
- To investigate Tip60's influence on DNA repair pathways and radiosensitivity.
Main Methods:
- Tip60 expression was downregulated using siRNA in A7 and MO59K glioma cell lines.
- Cell survival, DNA repair foci (γH2AX, Rad51, 53BP1, pATM), and interactions with ATM and DNA-PK were analyzed.
- Specific inhibitors for ATM (KU55933) and DNA-PK (NU7441) were used.
Main Results:
- Tip60 knockdown significantly reduced survival in both cell lines, particularly A7 cells.
- DNA-PK inhibition enhanced the radiosensitizing effect of Tip60 knockdown.
- Tip60 knockdown reduced initial Rad51 and ATM foci formation and prevented their dissolution post-irradiation.
Conclusions:
- Downregulating Tip60 enhances glioma cell radiation sensitivity, especially when combined with DNA-PK inhibitors.
- DNA-PK inhibitors represent a promising approach to synergistically augment radiation sensitivity in Tip60-deficient glioma cells.
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