Reversing intrinsic cancer cell resistance to alkylating agents by histone deacetylase inhibition

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Alkylating agents are ideal for the study of DNA damage triggered cell death, as the DNA lesions responsible for activating cell death along with the activated repair and damage response pathways have been elucidated in detail. This knowledge does, however, not explain why glioma cells differ so significantly in their survival following the induction of critical DNA lesions compared to non-transformed cells. The answer to this may be found in the histone deacetylase (HDAC) dependent deregulation of components of the DNA damage response, death execution and/or DNA repair pathways. As deregulation of the class I HDACs HDAC1 and HDAC3 do occur during the malignant transformation of glioblastoma, HDAC1 and HDAC3 may lead to anticancer drug resistance. However, whether or not the inhibition of class I HDACs has any effect on the intrinsic alkylating agent sensitivity of glioma cells is still a matter of debate. During the previous DFG funding period, I addressed the influence of class I HDACs on melanoma resistance. The data showed that HDAC2 stimulates the expression of the homologous recombination repair protein RAD51 and the Fanconi anaemia protein FANCD2, which causes resistance in melanomas to alkylating agents (Krumm et al. 2016, Roos and Krumm 2016). This resistance could be overcome by small molecule inhibition of class I HDACs. For gliomas, my preliminary data show that the inhibition of HDAC1 and HDAC2 with Entinostat (MS-275) sensitises glioma cells to alkylating agents, although the mechanism of sensitization differs from the mechanism we reported for melanoma cells. The preliminary data, in gliomas, points to a possible mechanism where overexpressed HDAC1 and/or HDAC3 causes resistance to the alkylating agent temozolomide (TMZ), due to the stimulation of a prolonged TMZ-induced DNA damage response. This causes the TMZ exposed glioma cells to enter a senescence-like state that protects them from initiating apoptosis. Upon co-treatment with the HDACi MS-275 and TMZ, the TMZ-induced DNA damage response is downregulated, gliomas no longer enter this senescence-like state and they become apoptotic. In this DFG-grant, I wish to focus on the mechanism of HDAC1/2/3 mediated resistance of glioma cells to alkylating agents and address the following specific questions. (1) Which of the class I HDACs causes the resistance of gliomas to alkylating agents? (2) What roles do HDAC1/2/3 play in the aberrant activation of the TMZ-triggered DNA damage response in glioma? Here the roles of HDAC1/2/3 on the histone acetyltransferase TIP60, the phosphatases PP2A and WIP1 as well as the epigenetic marks H3K56Ac and H4K91Ac will be addressed. (3) What roles do HDAC1/2/3 play in alkylating agent triggered senescence?