Role For Class Ⅰ Histone Deacetylases In Multidrug Resistance

The balance between acetylation and deacetylation in eukaryotic cells is critical for gene transcription and for the functions of different cellular proteins. The inhibition of histone deacetylase (HDAC) can alter the transcription of many tumor-associated genes and exhibit therapeutic activity against a variety of human malignancies, leading to phenotypic changes in the tumor, including growth arrest, proliferation, morphologic reversion, and apoptosis. Recent reports have showed that HDAC inhibitor resulted in multidrug resistance (MDR) to other chemotherapeutic agents. However, the molecular mechanisms of class I HDACs on MDR regulation are poorly understood. In this study, HDACl and HDAC2 acted as enhancers to intensify the chemosensitivities of anti-cancer drugs via reducing the expression levels of P-gp, MRP1 and MRP2. Furthermore, the dissociation of HDAC1 and HDAC2 led to transcriptional regulation of P-gp expression via the recruitment of p300, PCAF and NF-Y to the P-gp promoter region, which subsequently increased the level of the active gene marker, hyperacetylated histone H3. In parallel, selective inhibition of HDAC1 and HDAC2 induced the recruitment of p300, PCAF, NF-Y via acetylation of Sp1. Thus, our findings showed that HDAC1 and 2 regulated P-gp expression through dynamic changes in chromatin structure and transcription factor association within the promoter region.