Abstract 3355: Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells

Abstract

Abstract Tumors are suggested to be highly responsive to epigenetic alterations such as histone modifications and DNA methylation. We have previously reported a resistant phenotype of sphere-forming non-small cell lung cancer (NSCLC) tumor initiating cells (TICs) with an impaired activation of DNA-damage response proteins. Here we set out to analyze chromatin compactness since a heterochromatic structure has been postulated to constitute a barrier to DNA damage and repair. We show that certain NSCLC and small cell lung cancer (SCLC) TICs have elevated levels of the heterochromatin markers heterochromatin protein 1γ (HP1γ) and trimethylated lysine 9 of histone 3 (H3K9me3). Chromatin modulators were tested and histone deacetylase inhibitors (HDACi) vorinostat, panobinostat and trichostatin A reduced the cell viability of NSCLC TICs compared to bulk cells after 72 h. We could also demonstrate that TICs are more responsive to HDAC inhibitors since the euchromatin marker acetylated lysine 8 of histone H4 (H4K8ac) was increased after vorinostat and trichostatin A in NSCLC TICs but not in bulk cells. Pretreatment with HDACi inhibitors sensitized NSCLC TICs to cisplatin and ionizing irradiation. Accordingly, pretreatment with vorinostat increased the phosphorylation of the DNA-damage response proteins ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) upon irradiation in NSCLC TICs, whereas bulk cells already had a higher level with radiation only. In conclusion, we demonstrate that lung cancer TICs display a heterochromatic structure compared to bulk cells and that NSCLC TICs have an enhanced sensitization upon DNA damage inflicted by cisplatin or radiation after HDACi pretreatment. Citation Format: Lovisa Lundholm, Petra Hååg, Mina Eriksson, Beata Brzozowska, Rolf Lewensohn, Andrzej Wojcik, Kristina Viktorsson. Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3355.