Effects of retinoic acid and sodium butyrate on gene expression, histone acetylation and inhibition of proliferation of melanoma cells.

Retinoic acid (RA) induces growth-arrest of many tumor cell lines but it is an ineffective therapeutic against melanoma. We investigated whether the histone deacetylase (HDAC)-inhibitor sodium butyrate (BUT) can restore or potentiate the RA-response of RA-resistant human A375, and RA-responsive S91 murine melanoma cells. BUT induced expression of RARbeta and p21(waf1/cip1) mRNA in A375 cells but in S91 cells only p21(waf1/cip1) was induced. RA and BUT synergistically activated transcription of an RA-dependent reporter gene in S91, but not A375 cells. BUT increased histone H4-acetylation in both cell types. RA potentiated BUT-mediated inhibition of S91 cell proliferation, whereas A375 cells remained largely resistant to both compounds. HDAC-inhibitors may enhance the activity of RA on RA-responsive melanoma cells.