Retinoids have significant clinical activity in several human
cancers, yet the factors determining
retinoid sensitivity in
cancer cells are still unclear.
Retinoid-induced expression of
retinoic acid receptor (
RAR) beta(2) is a necessary component of the
retinoid anticancer signal in
cancer cells. We have previously identified the
Estrogen-responsive B Box
Protein (EBBP), a member of the Tripartite Motif (
TRIM) protein family, as a novel RARbeta2 transcriptional regulator in the
retinoid signal. Here we examined the mechanism of the EBBP effect on the
retinoid anticancer signal. We assessed
retinoid-responsive RARbeta2 transcription in
retinoid-resistant breast and
lung cancer cells in the presence of
chromatin modifying agents. A
histone deacetylase (
HDAC) inhibitor alone, or in combination with
retinoid, was more effective than a demethylating agent in restoring RARbeta2 transcription in resistant cells. Overexpression of EBBP alone markedly increased
histone acetylation. The effect of EBBP on
retinoid-responsive transcription appeared to be limited to genes with the
retinoic acid response element (betaRARE) regulatory sequence, such as
CYP26A1. EBBP inhibited cell growth by effects on
cyclin D1 and Phospho-Rb, and, reduced cell viability in
retinoid-resistant
cancer cells. The viability of non-
cancer cells was unaffected by EBBP overexpression. Taken together our data suggests that EBBP acts to de-repress transcription of RARbeta2 and
CYP26A1, by modifying
histone acetylation in
retinoid-resistant
cancer cells, and, is an important target for drug discovery in
retinoid-resistant
cancers.