Characterisation of the histone acetyltransferase KAT7 as a novel target for radiosensitisation

Thesis

Abstract:: Radiotherapy is one of the pillars of modern cancer therapy. However, side effects associated with normal tissue toxicity limit the effectiveness of this treatment. It is therefore desirable to develop tumour-specific radiosensitising agents, which can increase tumour cell kill without increasing the radiosensitivity of the surrounding normal tissue.

This project aimed at validating the radiosensitising potential of depletion of the histone acetyltransferase KAT7, and elucidating the underlying mechanism of action. My results showed a radiosensitising effect of KAT7 depletion in seven tumour cell lines. At the same time, a panel of normal tissue cell lines was not radiosensitised. The depletion of KAT7 caused general cell cycle changes, most notably a twofold increase in the proportion of mitotic cells. At the same time, the G2M checkpoint governing entry into mitosis appeared to be impaired. Livecell imaging confirmed a more than threefold increase in mitotic catastrophe following irradiation in KAT7-depleted cells. An oligonucleotide microarray also showed the downregulation of key members of the mitotic pathway, and patient data demonstrated higher expression of KAT7 to be associated with worse prognosis.

In summary, this project supports the tumour-specific radiosensitising potential of KAT7 depletion. This novel target for radiosensitisation seems to exert its effects through altering entry into and progression through mitosis.