Expression of acetyl-histone H4 in breast cancer

Abstract

Altered histone modifications are known to be observed in cancer cells. Acetylation of histone H4 (acetyl-H4) occurs reversibly on its amino-terminal end at four lysines positions 5, 8, 12 and 16 by Histone Acetyltransferase (HATs). Acetyl-H4 is responsible for a complex set of post-translational modifications that regulate the accessibility of DNA, transcription activation and DNA repair processes. Acetyl-H4 can also acetylate non-histone proteins which eventually control numerous cell signal pathways such as 53BP1, BRCA, AKT. Accumulated evidence showed that P13K, AKT controls the survival signaling pathway and is crucial in developing in drug resistance. This study investigates the global level of all lysine sites of acetyl-H4, its association with p-AKT as well as its prognostic significance in breast cancer.

The expression levels of acetyl-H4 were assessed by immunohistochemistry on 102 cases of breast cancer from Queen Mary Hospital in Hong Kong using tissue microarray technology. Nuclear expression of acetyl-H4 was scored and SPSS used for statistical analysis. p-AKT expression data previously obtained in our laboratory (Chen et al.) was also retrieved for correlation with nuclear acetyl-H4 scores. Nuclear acetyl-H4 scores were analyzed for association with a) various clinico-pathological parameters, b) luminal subtypes (ER-and PR-positive), HER-2-positive and triple negative breast cancer, c) p-AKT in breast cancer and d) patient survival by Kaplan-Meier analysis and Cox-regression.

By Pearson correlation test, we observed high acetyl-H4 expression was significantly associated with PR-positive breast cancer but not correlated with other clinical parameters and phenotypes of breast cancers (p>0.05). High acetyl-H4 expression was not correlated with p-AKT activity (p=0.84), although it showed inverse correlation with high nuclear p-AKT score. By Kaplan-Meier and Cox-regression analysis, high nuclear acetyl-H4 expression was significantly correlated with poor disease-specific survival in invasive ductal carcinoma (p=0.008 and 0.017 respectively). Multivariate Cox regression analysis confirmed high acetyl-H4 expression (p=0.047) when analyzed together with lymph node involvement (p=0.032) and T-stage (p=0.008) was an independent predictor of poor disease-specific survival in invasive ductal carcinoma.

Our results suggest that high acetyl-H4 expression is significantly associated with PR-positive phenotype and lower disease-free survival. The expression of acetyl-H4 was not correlated with p-AKT. Acetyl-H4 may be a potential biomarker to predict poor disease-specific survival for invasive ductal carcinoma. Further investigation is needed for possible use as therapeutic targeting for breast cancer.