Nuclear expression of histone deacetylases and their histone modifications predicts clinical outcome in colorectal cancer.

Abstract

Epigenetic changes are of crucial importance in cancer development and are potentially reversible; they are therefore targets of interest for anti-cancer therapy. The aim of this study was to investigate the clinical prognostic value of the histone deacetylases SIRT1, HDAC1 and HDAC2 and the histone modifications H4K16Ac and H3K56Ac in colorectal cancer. The epigenetic markers were immunohistochemically stained on tissue microarrays containing colorectal tumours (n = 254) and normal colorectal tissues (n = 50). Nuclear expression was assessed on the semi-automated Ariol system. Multivariate trend survival analyses of the combined markers showed better patient survival and less tumour recurrence when more markers showed high nuclear expression. For the combination of the histone deacetylases and H3K56Ac, the hazard ratio (HR) for overall survival (OS) was 0.82 [95% confidence interval (CI) 0.72-0.94; P = 0.005] and the HR for distant recurrence-free survival (DRFS) was 0.77 (95% CI 0.64-0.92; P = 0.003) per additional marker showing high expression. Similarly, for the combination of histone deactylases and H4K16Ac, HRs of 0.86 (95% CI 0.76-0.97; P = 0.01) for OS and 0.79 (95% CI 0.68-0.93; P = 0.006) for DRFS were observed per additional marker showing high expression. The studied epigenetic markers showed clinical prognostic value in colorectal cancer, both as individual markers and when combined into multimarker analyses. These results indicate that epigenetic mechanisms play an important role in colorectal carcinogenesis.