Résumé
IntroductionColorectal cancer (CRC) is the fourth most common cancer worldwide and even though the treatment has evolved, chemotherapy resistance is still a concern for therapy success and patients’ survival. Cell resistance may be modulated by several mechanisms, including epigenetic modifications; impacting gene expression and cell fate. The aim of this study was to identify epigenetic mechanisms that might control oxaliplatin cell resistance in CRC cells.Material and methodsGene expression-based risk score was built from the dataset of primary CRC samples of a cohort of 80 (Tisuji - GSE28702) and 36 (Del Rio - GSE72970), using 90 genes with epigenetic roles and defined as the sum of the Cox beta coefficients of each of the 25 genes found with a prognostic value (Episcore). Histones post-translational modifications (PTMs) were evaluated by mass spectrometry and drug interaction analysis was addressed by Sulforhodamine B test and Bliss equation.Results and discussionsEpiscore signature revealed 5 genes with a bad prognostic value (ATAD2, HDAC2, HDAC9, MBD1 and MBD2) and 20 with a good one (most of them histone methyltransferases). High-risk patients are characterised by a higher expression of the 5 bad prognostic genes and a lower expression of the 20 good ones. A maximum difference in OS was obtained with an Episcore at −6.098, splitting patients in Del Rio cohort into a high- and low-risk group of patients (score greater/less than −6.098, respectively) with 13.3 and 58 months median OS, respectively (p<0.0001). Episcore was also prognostic in Tsuji cohort (high-risk OS=12 months and low-risk median survival not reached) and when analysing the progression-free survival (patients treated only with FOLFOX regimen). We then evaluated histones PTMs in a 10-fold oxaliplatin resistant clone (HCT116-R1) compared with its parental HCT116 cells, treated or not with oxaliplatin. We found that resistant cells possess lower acetylation levels in histones 3 and 4 and oxaliplatin treatment decreased acetylation levels, for both cell lines. When combining the HDAC inhibitor Entinostat and oxaliplatin, we observed a synergistic effect in oxaliplatin-resistant cells HCT116-R1 and additive/antagonistic effects in the sensitive one.ConclusionThese findings confirm that epigenetic factors have an important prognostic and therapeutic value in patients with CRC. Hence, understanding the functional role of these genes/modifications in the pathogenesis and drug resistance of CRC is needed (already in progress in our group).