SETD1A‐mediated H3K4me3 methylation upregulates lncRNA HOXC‐AS3 and the binding of HOXC‐AS3 to EP300 and increases EP300 stability to suppress the ferroptosis of NSCLC cells

Autor: Zhenliang Shi, Hao Zhang, Yimeng Shen, Sipei Zhang, Xun Zhang, Yijun Xu, Daqiang Sun
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Thoracic Cancer, Vol 14, Iss 25, Pp 2579-2590 (2023)
Druh dokumentu: article
ISSN: 1759-7714
1759-7706
DOI: 10.1111/1759-7714.15037
Popis: Abstract Background Histone methyltransferases are crucial regulators in non‐small cell lung cancer (NSCLC) development. This study explored the mechanism of histone methyltransferase SET domain containing 1A (SETD1A)‐mediated H3K4me2 methylation in NSCLC cell ferroptosis and provides novel targets for NSCLC treatment. Methods Upon downregulation of SETD1A in NSCLC cell lines, cell proliferation potential, malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) activities, iron content, and SETD1A, long noncoding RNA HOXC cluster antisense RNA 3 (lncRNA HOXC‐AS3), E1A binding protein p300 (EP300), glutathione peroxidase 4 (GPX4) expressions were determined via cell counting kit‐8, ELISA, iron assay kits, RT‐qPCR, and western blot. Enrichment levels of SETD1A and H3K4me3 in the HOXC‐AS3 promotor were measured via chromatin immunoprecipitation, and the binding of HOXC‐AS3 and EP300 was analyzed via RNA immunoprecipitation. Rescue experiments were performed to confirm their roles in NSCLC cell ferroptosis. Xenograft tumor models were established to validate the role of SETD1A in vivo. Results SETD1A, H3K4me3, HOXC‐AS3, and EP300 were highly‐expressed in NSCLC cells. Silencing SETD1A inhibited NSCLC cell proliferation, increased MDA and iron levels, and decreased SOD, GSH, and GPX4 levels. SETD1A downregulation reduced H3K4me3 level, HOXC‐AS3 expression, the binding of HOXC‐AS3 to EP300, and EP300 stability. Overexpression of HOXC‐AS3 or EP300 reversed the promotion of silencing SETD1A on NSCLC cell ferroptosis. Silencing SETD1A reduced tumor volume and weight and positive rate of ki67 and increased ferroptosis through the HOXC‐AS3/EP300 axis. Conclusion SETD1A‐mediated H3K4me2 methylation promoted HOXC‐AS3 expression, binding of HOXC‐AS3 to EP300, and EP300 stability, thereby suppressing NSCLC cell ferroptosis.
Databáze: Directory of Open Access Journals
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