期刊
CELL DEATH & DISEASE
卷 12, 期 5, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-021-03760-2
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资金
- National Natural Science Foundation of China [82073384, 81772886, 81770933]
- Double Hundred Plan of Shanghai Jiao Tong University School of Medicine [20191812]
Through genomics, metabolomics, and RNA omics studies, it was discovered that inhibition of squalene epoxidase synergistically increased the sensitivity of HNSCC cells to EZH2 inhibitors, providing a basis for the development of new therapeutic strategies for HNSCC.
The histone methyltransferase EZH2 silences gene expression via H3 lysine 27 trimethylation and has been recognized as an important antitumour therapeutic target. However, the clinical application of existing EZH2 inhibitors is not satisfactory for the treatment of solid tumours. To discover novel strategies against head and neck squamous cell carcinoma (HNSCC), we performed genomics, metabolomics and RNA omics studies in HNSCC cells treated with EZH2 inhibitors. It was found that EZH2 inhibitors strongly induced the expression of genes in cholesterol synthesis. Through extensive drug screening we found that inhibition of squalene epoxidase (a key enzyme of endogenous cholesterol synthesis) synergistically increased the squalene content and enhanced the sensitivity of HNSCC cells to EZH2 inhibitors. Our findings provide an experimental and theoretical basis for the development of new combinations of EZH2 inhibitors to treat HNSCC.
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