Retinoids induce growth arrest, differentiation, and cell death in many
cancer cell types. One factor determining the sensitivity or resistance to the
retinoid anticancer signal is the transcriptional response of
retinoid-regulated target genes in
cancer cells. We used
cDNA microarray to identify 31
retinoid-regulated target genes shared by two
retinoid-sensitive
neuroblastoma cell lines, and then sought to determine the relevance of the target gene responses to the
retinoid anticancer signal. The pattern of
retinoid responsiveness for six of 13 target genes (RARbeta2,
CYP26A1, CRBP1, RGS16, DUSP6, EGR1) correlated with phenotypic
retinoid sensitivity, across a panel of
retinoid-sensitive or -resistant lung and
breast cancer cell lines.
Retinoid treatment of MYCN transgenic mice bearing
neuroblastoma altered the expression of five of nine target genes examined (RARbeta2,
CYP26A1, CRBP1, DUSP6, PLAT) in
neuroblastoma tumour tissue in vivo. In
retinoid-sensitive
neuroblastoma, lung and
breast cancer cell lines, direct inhibition of
retinoid-induced RARbeta2 expression blocked induction of only one of eight
retinoid target genes (
CYP26A1). DNA demethylation,
histone acetylation, and exogenous overexpression of RARbeta2 partially restored
retinoid-responsive
CYP26A1 expression in RA-resistant MDA-MB-231 breast, but not SK-MES-1
lung, cancer cells. Combined, rather than individual, inhibition of DUSP6 and RGS16 was required to block
retinoid-induced growth inhibition in
neuroblastoma cells, through phosphorylation of
extracellular-signal-regulated kinase. In conclusion, sensitivity to the
retinoid anticancer signal is determined in part by the transcriptional response of key
retinoid-regulated target genes, such as RARbeta2, DUSP6, and RGS16.