Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma

Xing Xu; Jun Chen; Yan Li; Xiaojie Yang; Qing Wang; Yanjun Wen; Ming Yan; Jianjun Zhang; Qin Xu; Yan Wei; Wantao Chen; Xu Wang

doi:10.1038/s41419-021-03760-2

Cell Death and Disease (May 2021)

Targeting epigenetic modulation of cholesterol synthesis as a therapeutic strategy for head and neck squamous cell carcinoma

Xing Xu,
Jun Chen,
Yan Li,
Xiaojie Yang,
Qing Wang,
Yanjun Wen,
Ming Yan,
Jianjun Zhang,
Qin Xu,
Yan Wei,
Wantao Chen,
Xu Wang

Affiliations

Xing Xu: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Jun Chen: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Yan Li: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Xiaojie Yang: Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Qing Wang: Department of Stomatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Yanjun Wen: Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Ming Yan: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Jianjun Zhang: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Qin Xu: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Yan Wei: Department of Ophthalmology, Shanghai Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
Wantao Chen: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology
Xu Wang: Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology

DOI: https://doi.org/10.1038/s41419-021-03760-2
Journal volume & issue: Vol. 12, no. 5
pp. 1 – 15

Abstract

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Abstract 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.

Published in Cell Death and Disease

ISSN: 2041-4889 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Science: Biology (General): Cytology
Website: http://www.nature.com/cddis/index.html

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