Role of SUV39H1 in ADAM17-mediated radioresistance
Sabine Bender, Ashish Sharma, Angela Broggini-Tenzer, Martin Pruschy
Laboratory for Molecular Radiobiology, Department of Radiation Oncology, University Hospital Zurich, Rämistrasse-100, 8091 ZurichSwitzerland,
The therapeutic response of ionizing radiation (IR) is imparted by genomic instability and DNA damage. However, IR also triggers intracellular signaling processes which lead to the secretion of various factors being involved in resistance mechanisms. Recently, we have shown that radiotherapy activates ADAM17 (A Disintegrin and metalloprotease domain 17) in NSCLC, which mediates IR-induced treatment resistance. Our new data point towards a link between ADAM17, chromatin remodeling via the histone methyltransferase SUV39H1 and the DNA damage response.
Radiotherapy activates ADAM17 in NSCLC, which results in shedding of multiple survival factors, growth factor pathway activation, and IR-induced treatment resistance. Inducible-shRNA-mediated silencing of ADAM17 or targeting of ADAM17 with the small molecular inhibitor TMI-005 suppressed IR-induced shedding of these factors, downregulated ErbB-signaling in target cells and enhanced IR-induced cytotoxicity in vitro and in vivo. Targeting of ADAM17 interfered with chromatin remodeling, decreased the basal level of SUV39H1 and abolished a short-term increase of the SUV39H1 protein in response to irradiation. Surprisingly decreased amounts of residual yH2AX were detected in ADAM17-depleted cells after irradiation despite their increased radiosensitivity in comparison to wildtype cells. At the same time, DNA damage signaling via Chk1 was impaired in ADAM17-deficient cells, implying a defect in the DNA repair machinery and poining towards a potential mechanism of radiosensitization by ADAM17 targeting.
Our findings demonstrate that IR significantly activates ADAM17, which results in shedding of survival factors, growth factor pathway activation and contributes to treatment resistance in NSCLC cells. Additionally, our data point towards a novel link between ADAM17, regulation of the chromatin state and the DNA damage response. We demonstrate that the impact of targeting ADAM17 is more pleiotropic than just diminishing ErbB signaling and provide a sound rationale for positioning ADAM17 inhibitors as radiosensitizers to improve the treatment of NSCLC.