Abstract
AbstractOrphan nuclear receptor NR2E3 activates p53 and induces cancer cell apoptosis. Further studies on p53-dependent and -independent functions of wild-type and mutatedNR2E3are needed. Herein, we showed that NR2E3 enhanced p53-DNA interactions in diverse cancer cells and up-regulated p53 and IFNα pathways while down-regulating MYC pathway in cervical cancer cells. Studies of “AllofUs” and TCGA databases showedNR2E3nonsynonymous mutations’ associating with four cancers. We stratifiedNR2E3SNVs for their cancer implications with the p53 reporter. A cancer-associatedNR2E3R97Hmutation not only lost the wild-type’s tumor-suppressing functions but also prohibited the wild-type from enhancing p53 acetylation. These observations implicated the potential for pharmaceutically activating NR2E3 to suppress cancer. Indeed, NR2E3’s small-molecule agonist 11a repressed 2-D and 3-D cultures of primary cells and cell lines of cervical cancer, in which screening FDA-approved anti-cancer drugs identified HDAC-1/2 inhibitor Romidepsin operating synergistically with 11a. The underlying molecular mechanisms included 11a’s down-regulating the transcription of Multidrug Resistance ProteinABCB1that Romidepsin up-regulated. Transcriptomics studies revealed three synergy modes: (1) “sum-up” mode that the p53 pathway activated individually by 11a and Romidepsin got stronger by the combo; (2) “antagonism” mode that Romidepsin counteracted the activation of the Kras pathway by 11a; and (3) “de novo” mode that the combo instead of each individual drug repressed the MYC pathway. Conclusively, our experiments provide new data supporting tumor-suppressor like functions for wild-typeNR2E3, reveal roles of mutatedNR2E3in cancer, and address values of NR2E3’s agonist 11a in cancer therapy alone and combined.
Publisher
Cold Spring Harbor Laboratory