Histone deacetylase inhibitor BML-210 induces growth inhibition and apoptosis and regulates HDAC and DAPC complex expression levels in cervical cancer cells

摘要

Histone deacetylase inhibitors (HDACIs) represent a new class of targeted anti-cancer agents and different other diseases, like muscular disorders. A number of studies have shown that extracellular signal-activated kinases can target chromatin-modifying complexes directly and regulate their function. The molecular connection between the dystrophin-associated protein complex (DAPC) and chromatin has been described, by showing that NO signaling regulates histone deacetylase (HDAC) activity and influences gene expression in different cell types. In present study, we investigated HDACs changes in HeLa cells undergoing growth inhibition and apoptosis, caused by HDACI BML-210 and retinoic acid (ATRA). Cell cycle analysis indicated that HeLa cell treatment with 20 and 30 μM concentration of BML-210 increased the proportion of cells in G0/G1 phase, and caused accumulation in subG1, indicating that the cells are undergoing apoptosis. We determined down-regulation of HDAC 1–5 and 7 after treatment with BML-210. Also, we demonstrated expression of different isoforms of alpha-dystrobrevin (α-DB) and other components of DAPC such as syntrophin, dystrophin, beta-dystrobrevin (β-DB) and NOS in HeLa cells after treatments. We determined changes in protein expression level of dystrophin, NOS1, α- and β-DB and in subcellular localization of α-DB after treatments with BML-210 and ATRA. In conclusion, these results suggest that HDACI BML-210 can inhibit cell growth and induce apoptosis in cervical cancer cells, what correlates with down-regulation of HDAC class I and II and changes in the DAPC expression levels. This can be important for identifying target proteins in DAPC signaling to HDACs, as a target of pharmacological intervention for treatment of muscular dystrophies and other diseases.