Influência das modificações pós-traducionais de histonas H3K4ME2, H3K4ME3 e H3K14AC no prognóstico e na sobrevida do carcinoma de células escamosas bucal

Abstract

Studies on epigenetics in oral squamous cell carcinoma (OSCC) are rare. Post-translational histone modifications (MPTHs) are essential regulators of gene expression and are deregulated in cancers. In this research we investigated the expression of demethylation of H3K4 (H3K4me2), trimethylation of H3K4 (H3K4me3) and acetylation of H3K14 (H3K14ac) in OSCC and their relationship with metastasis and survival. Paraffin-embedded tissue samples of 90 OSCC patients were raised and submitted to immunohistochemical staining with the antibodies against H3K4me2, H3K4me3 and H3K14ac. To determine their role in metastasis, OSCC patients were divided into two groups: primary non-metastatic tumors (PNM) and primary metastatic ones (PM). The nuclear MPTHs expression was measured according to the integrated optical density index (IOD) by using the software Image J. The expression of each MPTH was compared between the PNM and PM groups; correlation analyzes between them and the clinicopathological characteristics were also investigated. Sensitivity and specificity tests were established for each MPTH through the ROC curve; The ROC curve was also used to establish the cutoff point for each MPTH in order to distinguish high and low-expressing MPHT tumors. Survival curves and univariate and multivariate analyzes were also employed. All tumor cells were positive in the nucleus. Median H3K14ac expression was significantly higher in the PM group. An increased H3K4me3 expression was correlated with smoking, tumor differentiation and reduced survival. In addition, high levels of H3K4me3 had a negative impact on patient’s survival. The ROC curve showed that H3K14ac had the highest sensitivity (81.3%), suggesting that it might be used as a screening test for detecting N0 OSCC patients with great potential to develop metastasis during the course of their diseases. None of the MPTHs showed to be an independent prognostic factor in the multivariate analysis. A combination of MPTHs expression levels showed that low H3K4me2, high H3K4me3 and high H3k14ac expression significantly affected the patients’ survival from the PM group. In conclusion, our findings showed that H3K14ac was highly expressed in the PM group. High levels of H3K4me3 decreased the survival of patients and were correlated with tobacco use and less differentiated tumors.