Impaired retinoic acid (RA) signal leads to RARbeta2 epigenetic silencing and RA resistance

Resistance to the growth-inhibitory action of retinoic acid (RA), the bioactive derivative of vitamin A, is common in human tumors. One form of RA resistance has been associated with silencing and hypermethylation of the retinoic acid receptor ß2 gene (RARß2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RARß2 correlates with lack of the RA receptor {alpha} (RAR{alpha}). Normally, RAR{alpha} regulates RARß2 transcription by mediating dynamic changes of RARß2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RAR{alpha} (which was achieved by use of a dominant-negative RAR{alpha}, by downregulation of RAR{alpha} by RNA interference, and by use of RAR{alpha} antagonists) induces an exacerbation of the repressed chromatin status of RARß2 and leads to RARß2 transcriptional silencing. Further, we demonstrate that RARß2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RARß2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RARß2 through RAR{alpha} leads to RARß2 reactivation. This report provides proof of principle that RARß2 silencing and RA resistance are consequent to an impaired integration of RA signal at RARß2 chromatin.