Nuclear GRP75 Binds Retinoic Acid Receptors to Promote Neuronal Differentiation of Neuroblastoma

Retinoic acid (RA) has been approved for the differentiation therapy of neuroblastoma (NB). Previous work revealed a correlation between glucose-regulated protein 75 (GRP75) and the RA-elicited neuronal differentiation of NB cells. The present study further demonstrated that GRP75 translocates into the nucleus and physically interacts with retinoid receptors (RAR alpha and RXR alpha) to augment RA-elicited neuronal differentiation. GRP75 was required for RAR alpha/RXR alpha-mediated transcriptional regulation and was shown to reduce the proteasome-mediated degradation of RAR alpha/RXR alpha in a RA-dependent manner. More intriguingly, the level of GRP75/RAR alpha/RXR alpha tripartite complexes was tightly associated with the RA-induced suppression of tumor growth in animals and the histological grade of differentiation in human NB tumors. The formation of GRP75/RAR alpha/RXR alpha complexes was intimately correlated with a normal MYCN copy number of NB tumors, possibly implicating a favorable prognosis of NB tumors. The present findings reveal a novel function of nucleus-localized GRP75 in actively promoting neuronal differentiation, delineating the mode of action for the differentiation therapy of NB by RA.