ZNF184-mediated transcriptional activation of SAE1 drives the cell cycle entry and immune evasion in non-small cell lung cancer.

Abstract

Non-small cell lung cancer (NSCLC) is a highly prevalent subtype of lung cancer with an unsatisfactory prognosis, necessitating new therapeutic targets. The ubiquitin-like SUMO proteins covalently modify substrates and their functional properties. Here we report that SAE1 regulates p53 signaling through its ability to SUMOylate p53 and dissect the upstream modifiers of SAE1. Basal SAE1 levels were elevated in NSCLC cells, especially lung adenocarcinoma A549 and squamous cell carcinoma PC-10 lines. To probe SAE1 function, we utilized lentiviral short hairpin RNAs to stably knock down SAE1 in A549 and PC-10 cells. Knockdown of SAE1 significantly impeded the immune invasion in NSCLC in vitro and in vivo and promoted cell cycle arrest of NSCLC cells in vitro. Mechanistically, SAE1 knockdown suppressed p53 nuclear export and SUMOylation, while zinc finger protein 184 (ZNF184) with abnormally reduced methylation in NSCLC increased SAE1 transcription. Notably, the silencing of p53 rescued the immune evasion impeded by SAE1 knockdown, and SAE1 overexpression also rescued the antitumor benefits of sh-ZNF184. Overall, this study elucidates that abnormally reduced methylation of ZNF184 mediates transcriptional activation of SAE1 and impedes p53 expression through SUMOylation, thereby governing cell cycle arrest and promoting immune evasion in the NSCLC progression.