Affiliations: [a] Experimental Pathology Unit, National University Hospital, Copenhagen Biocenter, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark | [b] TopoTarget A/S, Symbion Science Park, Fruebjergvej 3, 2100 Copenhagen, Denmark | [c] Finsen laboratory, National University Hospital, Copenhagen Biocenter, Ole Maaloes Vej 5, 2200 Copenhagen, Denmark | [d] Department of Oncology, Finsen Centre, National University Hospital, 2100 Copenhagen, Denmark
Abstract: Histone deacetylase inhibitors (HDACi) are promising epigenetic cancer chemotherapeutics rapidly approaching clinical use. HDACi increases acetylation levels of histone and non-histone proteins and causes an alteration in gene-expression levels, ultimately resulting in proliferation arrest or apoptosis of especially cancer cells. However, the precise mechanism of action of this class of therapeutics and the genes implicated in sensitivity remain obscure. Hence, there is a need for identifying predictive biomarkers. In this study, we examined the gene-expression levels of selected possible HDACi biomarkers, as suggested in the literature. This was correlated with the inherent sensitivity towards the HDACi belinostat in a panel of 18 wild-type cancer cell lines with up to a 30-fold difference in chemosensitivity, which matched IC50 data from the NCI60 screen. Of 16 genes examined, 4 showed a correlation in their expression levels to belinostat sensitivity: Ornithine decarboxylase (ODC1), v-ski sarcoma viral oncogene homolog (SKI), signal transducer and activator of transcription 1 (STAT1), and thymidylate synthetase (TYMS). Including ODC and SKI simultaneously further strengthened the model. Further, there was no correlation between sensitivity and intracellular belinostat uptake or with histone and tubulin acetylation. Therefore, the genes identified in this study may be potential biomarkers for predicting clinical HDACi sensitivity.
Keywords: HDACi, belinostat, predictive biomarker, sensitivity, cancer cell panel
