The Estrogen-responsive B Box Protein Is a Novel Regulator of the Retinoid Signal

Abstract

Retinoic acid (RA) induces growth arrest, cell death, and differentiation in many human cancer cells in vitro and has entered routine clinical use for the treatment of several human cancer types. One mechanism by which cancer cells evade retinoid-induced effects is through repression of retinoic acid receptor ␤ (RAR␤) gene transcription. The RA response element ␤ (␤RARE) is the essential DNA sequence required for retinoid-induced RAR␤ transcription. Here we show that the estrogen-responsive B box protein (EBBP), a member of the RING-B box-coiled-coil protein family, is a ␤RARE-binding protein. EBBP undergoes serine threonine phosphorylation and enhanced protein stability after RA treatment. Following RA treatment, we also observed increased nuclear EBBP levels in aggregates with the promyelocytic leukemia protein at promyelocytic leukemia nuclear bodies. EBBP enhanced RA-responsive RAR␤ transcription in RA-sensitive and -resistant cancer cells, which were resistant to both a histone deacetylase inhibitor and a demethylating agent. EBBP-specific small interfering RNA reduced basal and RA-induced RAR␤ expression. EBBP increased ␤RARE-transactivating function through its coiled-coil domain. Taken together, our work suggests that EBBP may have a pivotal role in the retinoid anti-cancer signal.Over the past decade, basic and clinical research has demonstrated a therapeutic role for retinoids, in particular RA 2 in human cancer (1-3). Molecular events at the point of transcriptional regulation appear to be critical in determining cellular responses to retinoids. Upon entering the nucleus by simple diffusion, the retinoid ligand binds to retinoic acid receptors (RARs) or retinoid X receptors (each with ␣, ␤, and ␥ subtypes). The ligand-receptor complex initiates the retinoid signal by changes that occur at consensus DNA sequences or RA response elements (RAREs) in the regulatory 5Ј-untranslated sequence of so-called "target" genes.RAR␤ is a retinoid target with a well defined ␤RARE, which is necessary but not sufficient for the RA anti-cancer signal (4). Repression of basal or RA-induced RAR␤ transcription is a common event in a wide range of human tumor types, and numerous studies indicate that in specific circumstances RAR␤ acts as a tumor suppressor gene (2, 5-8).A frequent mechanism of RAR␤ repression is DNA methylation-induced silencing (9). Additionally, histone deacetylation is also associated with retinoid resistance, in the presence and absence of RAR␤2 hypermethylation, indicating that multiple mechanisms appear to contribute to RAR␤ repression (10).Intrinsic and acquired retinoid resistance has limited the clinical activity of retinoid-based therapy and chemoprevention. RA treatment in acute promyelocytic leukemia has been particularly valuable in illuminating mechanisms of retinoid resistance. Most acute promyelocytic leukemia cases present with the reciprocal t(15,17) translocation, resulting in the fusion product PML-RAR␣ (11). Dominant negative effects of the PML-RAR␣ fusion protein have been associated ...

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