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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 ␤2 gene (RAR␤2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RAR␤2 correlates with lack of the RA receptor ␣ (RAR␣). Normally, RAR␣ regulates RAR␤2 transcription by mediating dynamic changes of RAR␤2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RAR␣ (which was achieved by use of a dominantnegative RAR␣, by downregulation of RAR␣ by RNA interference, and by use of RAR␣ antagonists) induces an exacerbation of the repressed chromatin status of RAR␤2 and leads to RAR␤2 transcriptional silencing. Further, we demonstrate that RAR␤2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RAR␤2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RAR␤2 through RAR␣ leads to RAR␤2 reactivation. This report provides proof of principle that RAR␤2 silencing and RA resistance are consequent to an impaired integration of RA signal at RAR␤2 chromatin.

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