GRK 1739 - Research Projects
Project 3Sensitization to radiotherapy and chemotherapy by inhibition of epigenetic modifiers in lung cancer cell lines with loss of function mutations in SWI/SNF chromatin remodeling genes, or overexpression of EZH2
Prof. Dr. med. Martin Stuschke
Dr. rer. nat. Ali Sak
Dept. of Radiotherapy
Essen University Hospital
Summary
Chromatin remodeling complexes such as SWI/SNF factors are involved in cancer induction and are implicated in the regulation of gene expression and DNA damage-sensing. The histone methyltransferase EZH2 also interacts with proteins of the SWI/SNF complex. Modulation of EZH2 expression in the genetic background of the SWI/SNF subunits BRG1 or BRM can possibly influence radiation response of cancer cells. Downregulation of BRM inhibits clonogenic survival of BRG1 mutated cancer cells but not of wild type cells. The aim of the present study is to evaluate the role of chromatin remodeling factors (BRG1, BRM) on DDR after combined treatment schedules with cisplatin and EGFR inhibitors in cancer cell lines with epigenetic dysregulation. The results will help to develop targeted therapy options for tumors with dysfunctional chromatin remodeling factors. Overall, the present project emphasizes the role of chromatin structure in DNA damage response (DDR) and radiosensitivity, with molecular endpoints of DDR, such as DNA repair, cell cycle checkpoints, apoptosis and epigenetics.
Selected Publications
Zernickel, E., Sak A., Bannik K., Groneberg M., Stuschke M. Sensitization to radiotherapy by inhibition of epigenetic modifiers in non-small lung cancer cell lines with loss of function mutations in SWI/SNF chromatin remodeling genes. Strahlentherapie und Onkologie 2016; 192, S1, 37.
Bannik K, Sak A, Groneberg M, Stuschke M. Modulation of chromatin structure and its effect on radiation induced DNA damage signaling and survival. Strahlentherapie und Onkologie 2015; 191, S1, 77-78.
Sak A., Kübler D., Bannik K., Groneberg M., Stuschke M. Chromatin regulating proteins as a target for radiation therapy of glioma cell lines. Strahlentherapie und Onkologie 2016; 192, S1, 8.
Sak A, Kübler D, Bannik K, Groneberg M, Stuschke M. Dependence of radiation-induced H2AX phosphorylation on histone methylation: Evidence from the chromatin immunoprecipitation assay. Int J Radiat Biol 2015; 91:346-53.
Sak A, Grehl S, Engelhard M, Wierlemann A, Kaelberlah HP, Erichsen P, Pöttgen C, Groneberg M, Stuschke M. Long-term in vivo effects of cisplatin on gamma-H2AX foci signaling in peripheral lymphocytes of tumor patients after irradiation. Clin Cancer Res 2009; 15: 2927-34.