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Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote

Da-Wei Yeh1, Cheng Liu1, Juan Carlos Hernandez1

  • 1Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA.

Iscience
|July 14, 2023
PubMed

Insights

Alcohol and Hepatitis C Virus (HCV) co-infection promote liver cancer stemness by activating NANOG. Targeting the PRC2-NANOG interaction offers a new therapeutic strategy for hepatocellular carcinoma (HCC).

Area of Science:

  • Hepatocellular Carcinoma (HCC) Pathogenesis
  • Cancer Stem Cell Biology
  • Molecular Oncology

Background:

  • Alcohol and Hepatitis C Virus (HCV) synergistically promote hepatocellular carcinoma (HCC) through Toll-like receptor 4 (TLR4) signaling.
  • NANOG, a pluripotency transcription factor, is crucial for maintaining the stemness of tumor-initiating cells (TICs) in HCC.
  • NANOG, in complex with PRC2, suppresses oxidative phosphorylation (OXPHOS) gene expression, thereby generating TICs.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying alcohol and HCV-mediated HCC development.
  • To investigate the role of NANOG and its interaction with the PRC2 complex in TIC generation.
  • To identify novel therapeutic targets for HCC treatment.

Main Methods:

  • Investigated the synergistic effects of alcohol and HCV on TLR4 signaling and NANOG activation.
  • Analyzed the interaction between NANOG, PRC2 complex (EED, EZH2, SUZ12), and the PEST domain.
  • Utilized CRISPR-Cas9-mediated ARID1A knockout and CTNNB1 mutations in humanized FRG HCC mouse models.
  • Assessed the efficacy of PRC2-NANOG interface inhibitors and FAO inhibitors in blocking tumor growth.

Main Results:

  • Alcohol and HCV synergistically activate NANOG via TLR4 signaling, promoting HCC stemness.
  • NANOG protein stability is regulated by its PEST domain binding to EED, preventing proteasomal degradation.
  • Human ARID1A loss confers resistance to FAO and PRC2 inhibition by reducing mitochondrial ROS.
  • CRISPR-Cas9-mediated ARID1A knockout and CTNNB1 mutations promote HCC development.
  • Inhibiting the PRC2-NANOG interaction or FAO effectively blocks tumor growth in mouse models.

Conclusions:

  • The PRC2-NANOG interaction is a critical driver of HCC stemness and tumor development.
  • Targeting the PRC2-NANOG interaction represents a promising therapeutic strategy for HCC.
  • Inducing differentiation-related genes and destabilizing NANOG protein can suppress HCC progression.
Keywords:
Molecular physiologyStem cells research

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