Loss of class III beta-tubulin induced by histone deacetylation is associated with chemosensitivity to paclitaxel in malignant melanoma cells

Abstract

Overexpression of class III beta-tubulin (TUBB3) is an important mechanism of taxane resistance. Using 7 melanoma cell lines, 2 normal neonatal human epidermal melanocyte (NHEM) cultures, and 49 primary melanomas, we investigated TUBB3 expression, its relationship to chemosensitivity to taxane derivatives, and the epigenetic mechanism controlling TUBB3 gene expression. Normal melanocytes in vitro and in vivo strongly expressed TUBB3 protein. NHEMs exhibited marked chemoresistance to paclitaxel-induced apoptosis. A subset (10 of 49, 20%) of primary malignant melanomas was TUBB3 negative. The incidence of TUBB3-negative melanomas increased with stage of progression. TUBB3 protein expression varied among cell lines; one (HMV-I) of the seven cell lines exhibited an extremely low endogenous level. TUBB3 protein expression correlated well with chemosensitivity to paclitaxel-induced apoptosis (P<0.05). Treatment with a histone deacetylase (HDAC) inhibitor restored TUBB3 expression in HMV-I. Chromatin immunoprecipitation assays revealed that histones H3 and H4 were hypoacetylated at the TUBB3 gene in HMV-I as compared with a TUBB3-overexpressing cell type (HMV-II). Treatment with the HDAC inhibitor induced gain of histone acetylation only in HMV-I. These results suggest that loss of TUBB3 protein may be induced by histone deacetylation in a subset of malignant melanomas, and may be associated with chemosensitivity to taxane.