The Loss of an orphan Nuclear Receptor augments Wnt/β-Catenin signaling via epigenetic dysregulation that promotes Sp1 and Myc interactions in Hepatocellular Carcinoma Development [RNA-seq]

We previously reported that the nuclear receptor NR2E3 activates the tumor suppressor gene p53 by modulating chromatin accessibility. In this study, we further investigated the impact of NR2E3 deficiency on chromatin accessibility. We used FAIRE-seq (Formaldehyde-Assisted Isolation of Regulatory Elements) analysis to find that NR2E3 loss increased chromatin accessibility in genomic regions interacting with various transcription factors, including Sp1. Additionally, NR2E3 loss enhanced chromatin accessibility and expression of crucial genes, such as JAK1 and PPARD, essential for WNT-β-catenin signaling pathway activation by facilitating interactions between Sp1 and Myc transcription factors at their promoters. Gene set enrichment analysis (GSEA) on mouse liver tumor tissues from wild-type and NR2E3 knockout mice confirmed that NR2E3 ablation activated WNT-β-catenin signaling pathways in vivo. Kaplan-Meier survival analysis using liver cancer patient data from two clinical datasets confirmed that patients with low NR2E3 expression exhibited increased WNT-β-catenin signaling activation, associated with adverse clinical outcomes. These findings highlight NR2E3 as a crucial tumor suppressor gene in hepatocellular carcinoma (HCC), primarily restraining WNT-β-catenin signaling pathway activation to maintain epigenetic homeostasis and contribute to HCC development. Our results prove NR2E3's critical role in liver cancer pathogenesis by regulating WNT-β-catenin signaling pathways and epigenetic equilibrium maintenance. RNA-seq with WT and NR2E3 KO Liver Tumors