Impaired retinoic acid (RA) signal leads to RARβ2 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 β2 gene (RARβ2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RARβ2 correlates with lack of the RA receptor α (RARα). Normally, RARα regulates RARβ2 transcription by mediating dynamic changes of RARβ2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RARα (which was achieved by use of a dominant-negative RARα, by downregulation of RARα by RNA interference, and by use of RARα antagonists) induces an exacerbation of the repressed chromatin status of RARβ2 and leads to RARβ2 transcriptional silencing. Further, we demonstrate that RARβ2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RARβ2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RARβ2 through RARα leads to RARβ2 reactivation. This report provides proof of principle that RARβ2 silencing and RA resistance are consequent to an impaired integration of RA signal at RARβ2 chromatin.