RETRACTED: Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal

Jul 14, 2023iScience

Polycomb repressive complex 2 supports stem cell renewal by stabilizing NANOG and blocking differentiation genes

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Abstract

The interaction between PRC2 and NANOG may serve as a new drug target for hepatocellular carcinoma (HCC).

Alcohol and HCV activate NANOG through TLR4 signaling, which is important for the development of tumor-initiating stem-like cells.
NANOG, along with the PRC2 complex, inhibits genes involved in energy production to support the growth of these cancer cells.
NANOG protein stability is enhanced by its binding to EED, preventing its degradation.
Loss of the human ARID1A gene may lead to resistance against therapies targeting fatty acid oxidation and PRC2.
In mouse models of HCC, disrupting the PRC2-NANOG interaction or inhibiting fatty acid oxidation effectively halted tumor growth.

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The synergistic effect of alcohol and HCV mediated through TLR4 signaling transactivates NANOG, a pluripotency transcription factor important for the stemness of tumor-initiating stem-like cells (TICs). NANOG together with the PRC2 complex suppresses expression of oxidative phosphorylation (OXPHOS) genes to generate TICs. The phosphodegron sequence PEST domain of NANOG binds EED to stabilize NANOG protein by blocking E3 ligase recruitment and proteasome-dependent degradation, while the tryptophan-rich domain of NANOG binds EZH2 and SUZ12. Human ARID1A gene loss results in the resistance to combined FAO and PRC2 inhibition therapies due to reduction of mitochondrial ROS levels. CRISPR-Cas9-mediatedknockout and/or constitutively activedriver mutations promoted tumor development in humanized FRG HCC mouse models, in which use of an interface inhibitor antagonizing PRC2-NANOG binding and/or FAO inhibitor blocked tumor growth. Together, the PRC2-NANOG interaction becomes a new drug target for HCC via inducing differentiation-related genes, destabilizing NANOG protein, and suppressing NANOG activity. ARID1A CTNNB1

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RETRACTED: Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal

Abstract

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