Nuclear localized GRP75 binds to retinoic acid receptors (RAR/RXR) and promotes retinoic acid‐induced neuronal differentiation of neuroblastoma

Abstract

Neuroblastoma (NB) is the most common and deadly extracranial solid tumor in children. Retinoic acid (RA) has been used in clinic to treat NB by inducing neuronal differentiation of tumor cells. We previously found that glucose‐regulated protein 75 (GRP75) is correlated with the RA‐elicited neuronal differentiation of NB cells. In the present study, we further demonstrated that GRP75 can be translocated into nucleus and interact with retinoic acid receptor (RAR)α and retinoid X receptor (RXR)α to augment RA‐elicited neuronal differentiation. Down‐regulation of GRP75 diminishes the recruitment of RARα/RXRα to the retinoic acid response element (RARE) in the regulatory region of RA target gene promoters, resulting in a significant decrease in RA‐triggered gene expression. GRP75 also plays an essential role in stabilizing RARα/RXRα complexes in the presence of RA by reducing the proteasome‐mediated degradation of RARα and RXRα. Most intriguingly, the interaction between GRP75 and RARα/RXRα receptors was tightly associated with favorable outcome in NB patients and in a xenograft NB mouse model. Together, our present findings delineate a mechanism underlying the GRP75‐dependent regulation of RARα/RXRα‐mediated gene expression in the RA‐induced neuronal differentiation of NB, providing the basis for the development of novel therapeutics for NB. Grant Funding Source : Academia Sinica