Histone deacetylase inhibitors increase p21(WAF1) and induce apoptosis of human myeloma cell lines independent of decreased IL-6 receptor expression

Histone deacetylase (HDAC) inhibitors cause growth arrest and apoptosis of cancer cells by both p21-dependent and independent mechanisms. Decreased ex pression of growth factor receptors may be a key factor in the p21-independ ent mechanism, although this has not been directly tested. We have tested t he effects of sodium butyrate and trichostatin A on human myeloma cell line s and have observed GI arrest and apoptosis associated with increased expre ssion of p21(WAF1), Bax, Rb dephosphorylation, and decreased IL-6 receptor (IL-6R) expression. Experiments to determine the role of disruption of IL-6 signaling as a result of decreased IL-6 receptor expression in mediating t hese effects were conducted using a stable transfectant of the OPM-2 line w hich constitutively expressed the IL-6 receptor. Our results indicated that decreased IL-6R expression was not required for induction of p21(WAF1) or apoptosis. Thus, HDAC inhibitors appear to activate multiple cellular pathw ays, leading to growth arrest and apoptosis, and their use in the treatment of myeloma, particularly in combination with other agents, warrants furthe r investigation. (C) 2001 Wiley-Liss, Inc.