LncRNA UCA1 Antagonizes Arsenic-Induced Cell Cycle Arrest through Destabilizing EZH2 and Facilitating NFATc2 Expression.

Abstract

Arsenic (As) is a widespread metalloid contaminant, and its internal exposure is demonstrated to cause serious detrimental health problems. Albeit considerable studies are performed to interrogate the molecular mechanisms responsible for As‐induced toxicities, the exact mechanisms are not fully understood yet, especially at the epigenetic regulation level. In the present study, it is identified that long non‐coding RNA (lncRNA) urothelial cancer associated 1 (UCA1) alleviates As‐induced G2/M phase arrest in human liver cells. Intensive mechanistic investigations illustrate that UCA1 interacts with enhancer of zeste homolog 2 (EZH2) and accelerates the latter's protein turnover rate under normal and As‐exposure conditions. The phosphorylation of EZH2 at the Thr‐487 site by cyclin dependent kinase 1 (CDK1) is responsible for As‐induced EZH2 protein degradation, and UCA1 enhances this process through increasing the interaction between CDK1 and EZH2. As a consequence, the cell cycle regulator nuclear factor of activated T cells 2 (NFATc2), a downstream target of EZH2, is upregulated to resist As‐blocked cell cycle progress and cytotoxicity. In conclusion, the findings decipher a novel prosurvival signaling pathway underlying As toxicity from the perspective of epigenetic regulation: UCA1 facilitates the ubiquitination of EZH2 to upregulate NFATc2 and further antagonizes As‐induced cell cycle arrest.