Abstract
Simple SummaryNuclear receptor related-1 protein (Nurr1) emerges as a therapeutic target in multiple malignancies and immunotherapies. Previous studies have highlighted its association with clinicopathological parameters, tumorigenesis and therapeutic resistance in cancers. In addition, recent studies unraveled its contribution to the suppression of antitumor immunity, suggesting that inhibition of Nurr1 is a potential method to repress cancer aggressiveness and disrupt tumor immune tolerance. In line with this evidence, the present review provides the roles of Nurr1 in tumor progression and the associated underlying molecular mechanisms. Moreover, the significance of Nurr1 in promoting immune tolerance and potential strategies for Nurr1 inhibition are highlighted. Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.
Highlights
Nuclear receptor related-1 protein (Nurr1), known as NR4A2, belongs to the nuclear receptor (NR) subfamily 4 group A (NR4A)
Nurr1-mediated transcription remains unknown, mounting evidence suggests that post-translational organization with ≈91–95% similarity in their DNA binding domain (DBD) and ≈60% similarity interactions are crucial in transcriptional regulationdomain and thatofthe
Nurr1 induces gene expression by binding as a monomer to the Besides, the C-terminal domain is composed of ligand-binding domain (LBD) and the ligand-dependent activation function-2 nerve (Figure growth1A)
Summary
Nuclear receptor related-1 protein (Nurr1), known as NR4A2, belongs to the nuclear receptor (NR) subfamily 4 group A (NR4A). Nurr is classified as an ‘orphan’ NR due to the absence of known natural ligands [1] These NRs are considered as early response genes that respond to many different signals, including fatty acids and hormones [2]. C-terminal domain is composed of LBD and the ligand-dependent activation function-2. Nurr1-mediated transcription remains unknown, mounting evidence suggests that post-translational organization with ≈91–95% similarity in their DNA binding domain (DBD) and ≈60% similarity interactions are crucial in transcriptional regulationdomain and thatofthe. Nurr induces gene expression by binding as a monomer to the Besides, the C-terminal domain is composed of LBD and the ligand-dependent activation function-2 nerve (Figure growth1A). Unlike conventional NRs, which have a hydrophobic cleft in the LBD for binding of ato the Nur orresponse element (NurRE; 5′-TGACCTTT-n6-AAAGGTCA-3′). Nurr is considered a constitutively active transcription factor due to the constitutive and
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