Abstract
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 devel
opment.