Nr1d2, also known as REV-ERB-β, is a nuclear hormone receptor and an essential component of the circadian clock, regulating the expression of core clock proteins that drive rhythms in activity and metabolism [4,5]. It has been implicated in multiple biological processes and disease-related pathways, such as Hippo and Notch pathways [2].

In cancer research, depletion of Nr1d2 in HCC cells decreased their proliferation, migration and invasion both in vitro and in vivo, with fewer metastatic nodules in the lungs. It also affected the epithelial-to-mesenchymal transition (EMT) by amplifying epithelial marker E-cadherin and decreasing mesenchymal markers N-cadherin and vimentin [1]. In glioblastoma, silencing of Nr1d2 inhibited cell proliferation and motility, and identified AXL as a new transcriptional target, which mediated some of Nr1d2's regulatory effects on the PI3K/AKT axis [3]. In melanoma, LINC01224 upregulated Nr1d2 expression by sponging miR-193a-5p, facilitating cell proliferation and inhibiting radiosensitivity [6]. In sepsis-induced cardiomyopathy, mesenchymal stem cells alleviated the condition by down-regulating the expression of Nr1d2 and its downstream target gene LCN2 [7].

In conclusion, Nr1d2 is crucial for regulating circadian rhythm and metabolism. Its dysregulation is associated with cancer progression and other diseases like sepsis-induced cardiomyopathy. Studies using gene-knockdown or knockout models have revealed its role in processes such as cell proliferation, invasion, and EMT in cancer, providing insights into potential therapeutic strategies for these diseases.

References:

1. Tong, Hui, Liu, Xiaohui, Li, Tao, Shen, Baiyong, Zhu, Zhecheng. 2020. NR1D2 Accelerates Hepatocellular Carcinoma Progression by Driving the Epithelial-to-Mesenchymal Transition. In OncoTargets and therapy, 13, 3931-3942. doi:10.2147/OTT.S237804. https://pubmed.ncbi.nlm.nih.gov/32440156/

2. Wang, Xianping, Guo, Yifan, Lin, Peng, Xie, Qi, Ma, Xianjue. 2024. Nuclear receptor E75/NR1D2 promotes tumor malignant transformation by integrating Hippo and Notch pathways. In The EMBO journal, 43, 6336-6363. doi:10.1038/s44318-024-00290-3. https://pubmed.ncbi.nlm.nih.gov/39516282/

3. Yu, Min, Li, Wenjing, Wang, Qianqian, Wang, Yan, Lu, Fei. 2018. Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility. In Oncogene, 37, 4838-4853. doi:10.1038/s41388-018-0319-8. https://pubmed.ncbi.nlm.nih.gov/29773903/

4. Sulli, Gabriele, Rommel, Amy, Wang, Xiaojie, Verma, Inder M, Panda, Satchidananda. 2018. Pharmacological activation of REV-ERBs is lethal in cancer and oncogene-induced senescence. In Nature, 553, 351-355. doi:10.1038/nature25170. https://pubmed.ncbi.nlm.nih.gov/29320480/

5. Cho, Han, Zhao, Xuan, Hatori, Megumi, Panda, Satchidananda, Evans, Ronald M. 2012. Regulation of circadian behaviour and metabolism by REV-ERB-α and REV-ERB-β. In Nature, 485, 123-7. doi:10.1038/nature11048. https://pubmed.ncbi.nlm.nih.gov/22460952/

6. Cui, Yu, Zheng, Yi, Lu, Yue, Yang, Lei, Li, Wei. 2021. LINC01224 facilitates the proliferation and inhibits the radiosensitivity of melanoma cells through the miR-193a-5p/NR1D2 axis. In The Kaohsiung journal of medical sciences, 38, 196-206. doi:10.1002/kjm2.12467. https://pubmed.ncbi.nlm.nih.gov/34783160/

7. Jiang, Cheng, Wang, Shengbao, Wang, Cunbao, Xu, Jing, You, Chongge. 2024. Mesenchymal Stem Cells Alleviate Mouse Sepsis-Induced Cardiomyopathy by Inhibiting the NR1D2/LCN2 Pathway. In Journal of cardiovascular pharmacology, 84, 199-209. doi:10.1097/FJC.0000000000001590. https://pubmed.ncbi.nlm.nih.gov/39115719/