Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer

Khanal, Tilak; Choi, Kwangmin; Leung, Yuet-Kin; Jiang, Wang; Kim, Dasom; Janakiram, Vinothini; Cho, Sung Gook; Puga, Alvaro; Ho, Shuk‐Mei; Kim, Kyounghyun

doi:10.1038/s41598-017-11106-2

Cited by 20 publications

(32 citation statements)

References 68 publications

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“…Liver tissue lysate from the founder mice showed the absence of Nr2e3 expression by immunoblotting. Consistent to the previous results (9), Nr2e3 ablation in vivo decreased Ahr protein and mRNA expressions with no alteration in the basal p53 levels (Fig. 1C, D).…”

Section: Crispr/cas9-mediated Nr2e3 Gene Ablation In Vivosupporting

confidence: 92%

“…We further demonstrated that NR2E3 formed active transcriptional complex with specificity protein 1 (Sp1) transcription factor and maintained the basal expression of aryl hydrocarbon receptor (AHR) by preventing LSD1-mediated epigenetic reprogramming. We also showed that NR2E3 loss is also correlated with the development of human liver diseases and cancer (9).…”

mentioning

confidence: 54%

“…Therefore, we investigated whether NR2E3 loss could also dysregulate the epigenetic status of DINO. It was previously reported that NR2E3 formed an active complex with Sp1 transcription factor to sustain active AHR epigenetic status and its expression (9). Interestingly, the result from an online promoter analysis showed that there are 2 consensus Sp1 binding sites in the proximal DINO gene promoter region (33) (Fig.…”

Section: Nr2e3 Loss Induced Repressive Dino Epigenetic Status With Rementioning

confidence: 86%

“…Our previous reports showed that NR2E3 played a role in maintaining the active epigenetic status of ER and AHR gene promoters, the depletion of which resulted in epigenetic repression (8,9). Therefore, we investigated whether NR2E3 loss could also dysregulate the epigenetic status of DINO.…”

Section: Nr2e3 Loss Induced Repressive Dino Epigenetic Status With Rementioning

confidence: 92%

“…Our previous report showed that NR2E3 loss is clinically associated with development of liver diseases and cancer (9), the end points of many liver injuries. Thus, we first examined the role of NR2E3 by employing a typical liver toxicant APAP.…”

Section: Crispr/cas9-mediated Nr2e3 Gene Ablation In Vivomentioning

confidence: 99%

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NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries

et al. 2019

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Damage‐induced long noncoding RNA (DINO) is a long noncoding RNA that directly interacts with p53 and thereby enhances p53 stability and activity in response to various cellular stresses. Here, we demonstrate that nuclear receptor subfamily 2 group E member 3 (NR2E3) plays a crucial role in maintaining active DINO epigenetic status for its proper induction and subsequent p53 activation. In acetaminophen (APAP)‐ or carbon tetrachloride‐induced acute liver injuries, NR2E3 knockout (KO) mice exhibited far more severe liver injuries due to impaired DINO induction and p53 activation. Mechanistically, NR2E3 loss both in vivo and in vitro induced epigenetic DINO repression accompanied by reduced DINO chromatin accessibility. Furthermore, compared with the efficient reversal by a typical antidote N‐acetylcysteine (NAC) treatment of APAP‐induced liver injury in wild‐type mice, the liver injury of NR2E3 KO mice was not effectively reversed, indicating that an intact NR2E3‐DINO‐p53–signaling axis is essential for NAC‐mediated recovery against APAP‐induced hepatotoxicity. These findings establish that NR2E3 is a critical component in p53 activation and a novel susceptibility factor to drug‐ or toxicant‐induced acute liver injuries.—Khanal, T., Leung, Y.‐K., Jiang, W., Timchenko, N., Ho, S.‐M., Kim, K. NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries. FASEB J. 33, 8335–8348 (2019). http://www.fasebj.org

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Section: Crispr/cas9-mediated Nr2e3 Gene Ablation In Vivosupporting

confidence: 92%

mentioning

confidence: 54%

Section: Nr2e3 Loss Induced Repressive Dino Epigenetic Status With Rementioning

confidence: 86%

Section: Nr2e3 Loss Induced Repressive Dino Epigenetic Status With Rementioning

confidence: 92%

Section: Crispr/cas9-mediated Nr2e3 Gene Ablation In Vivomentioning

confidence: 99%

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NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries

et al. 2019

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The Loss of an Orphan Nuclear Receptor NR2E3 Augments Wnt/β‐catenin Signaling via Epigenetic Dysregulation that Enhances Sp1‐β catenin‐p300 Interactions in Hepatocellular Carcinoma

Leung,

Lee,

Wang

et al. 2024

Advanced Science

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The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3) is an epigenetic player that modulates chromatin accessibility to activate p53 during liver injury. Nonetheless, a precise tumor suppressive and epigenetic role of NR2E3 in hepatocellular carcinoma (HCC) development remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β‐catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice consistently exhibits accelerated liver tumor formation accompanied by enhanced activation of Wnt/β‐catenin signaling pathway and inactivation of p53 signaling. At cellular level, the loss of NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates key genes in the WNT/β‐catenin pathway with increased chromatin accessibility. This event is mediated through increased formation of active transcription complex involving Sp1, β‐catenin, and p300, a histone acetyltransferase, on the promoters of target genes. These findings demonstrate that the loss of NR2E3 activates Wnt/β‐catenin signaling at cellular and organism levels and this dysregulation is associated with aggressive HCC development and poor clinical outcomes. In summary, NR2E3 is a novel tumor suppressor with a significant prognostic value, maintaining epigenetic homeostasis to suppress the Wnt/β‐catenin signaling pathway that promotes HCC development.

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Targeting Nr2e3 to Modulate Tet2 Expression: Therapeutic Potential for Depression Treatment

Ma,

Xu,

Zhou

et al. 2024

Advanced Science

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Epigenetic mechanisms such as DNA methylation and hydroxymethylation play a significant role in depression. This research has shown that Ten‐eleven translocation 2 (Tet2) deficiency prompts depression‐like behaviors, but Tet2's transcriptional regulation remains unclear. In the study, bioinformatics is used to identify nuclear receptor subfamily 2 group E member 3 (Nr2e3) as a potential Tet2 regulator. Nr2e3 is found to enhance Tet2's transcriptional activity by binding to its promoter region. Nr2e3 knockdown in mouse hippocampus leads to reduced Tet2 expression, depression‐like behaviors, decreased hydroxymethylation of synaptic genes, and downregulation of synaptic proteins like postsynaptic density 95 KDa (PSD95) and N‐methy‐d‐aspartate receptor 1 (NMDAR1). Fewer dendritic spines are also observed. Nr2e3 thus appears to play an antidepressant role under stress. In search of potential treatments, small molecule compounds to increase Nr2e3 expression are screened. Azacyclonal (AZA) is found to enhance the Nr2e3/Tet2 pathway and exhibited antidepressant effects in stressed mice, increasing PSD95 and NMDAR1 expression and dendritic spine density. This study illuminates Tet2's upstream regulatory mechanism, providing a new target for identifying early depression biomarkers and developing treatments.

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Loss of NR2E3 represses AHR by LSD1 reprogramming, is associated with poor prognosis in liver cancer

Cited by 20 publications

References 68 publications

NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries

NR2E3 is a key component in p53 activation by regulating a long noncoding RNA DINO in acute liver injuries

The Loss of an Orphan Nuclear Receptor NR2E3 Augments Wnt/β‐catenin Signaling via Epigenetic Dysregulation that Enhances Sp1‐β catenin‐p300 Interactions in Hepatocellular Carcinoma

Targeting Nr2e3 to Modulate Tet2 Expression: Therapeutic Potential for Depression Treatment

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