The retinoid anticancer signal: mechanisms of target gene regulation

Abstract

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 (RARb2, 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 (RARb2, 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 RARb2 expression blocked induction of only one of eight retinoid target genes (CYP26A1). DNA demethylation, histone acetylation, and exogenous overexpression of RARb2 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 extracellularsignal-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 RARb2, DUSP6, and RGS16.

ATP7A is a novel target of retinoic acid receptor β2 in neuroblastoma cells

“…Previous studies focused on the role of ATP7A in Menke's disease, have shown that ATP7A expression and copper plays an important role in neural differentiation and neuritogenesis (El Meskini et al, 2005Birkaya and Aletta, 2005). We found an increase in cell viability when ATP7A expression was knocked down in neuroblastoma cells (Liu et al, 2005). The significant correlation between ATP7A and RARb expression suggests that ATP7A may contribute to the RARb anti-cancer therapeutic effect.…”

“…In a previous study using the cDNA microarray, we found that the copper transporter ATP7A was strongly upregulated in neuroblastoma cells in response to retinoid (Liu et al, 2005). In this study, we found that ATP7A protein expression is upregulated in neuroblastoma cells after retinoid treatment.…”

“…We have previously identified the copper efflux pump protein, ATP7A, as a retinoid-regulated gene using a cDNA microarray analysis of retinoid-treated neuroblastoma cells (Liu et al, 2005). Here, we examined the hypotheses that RARb 2 may regulate ATP7A, and, that ATP7A may be responsible for the growth suppressive effects of RARb 2 in neuroblastoma cells.…”

“…We have previously identified the copper metabolism gene ATP7A as a retinoid-regulated gene in neuroblastoma cell lines (Liu et al, 2005). In non-neuronal cells, ATP7A is responsive to levels of intracellular copper, and is predominantly localised to the trans-Golgi network when cytosolic copper levels are normal or low.…”

A novel role for the retinoic acid-catabolizing enzyme CYP26A1 in Barrett's associated adenocarcinoma

“…CYP26A1 has been shown to be upregulated in human familial adenomatous polyposis adenomas, sporadic colon cancers and primary ovarian cancer (Downie et al, 2005;Shelton et al, 2006). Furthermore, the pattern of retinoid gene expression, including CYP26A1, has been shown to correlate with retinoid sensitivity in a panel of breast and lung cancer cell lines (Liu et al, 2005).…”