Orphan nuclear receptorNR2E3and its small-molecule agonist induce cancer cell apoptosis through regulating p53, IFNα and MYC pathways

Author:

Wang Yidan,Kroll Todd,Hao Linhui,Sharma Ansul,Zhou Vivian,Moat Luke,Mayer John,Shukla Sanjay S.,Hebbring Scott,Guo Song,Iden Marissa,Bissonnette Adam,Ananiev Gene,Parashar Deepak,Rader Janet S.,Janz Siegfried,Wen ZhiORCID

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

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