Affiliation:
1. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263
Abstract
ABSTRACT
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
RAR
β
2
correlates with lack of the RA receptor α (RARα). Normally, RARα regulates
RARβ2
transcription by mediating dynamic changes of
RAR
β
2
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.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
54 articles.
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