Upregulation of deubiquitinase USP7 by transcription factor FOXO6 promotes EC progression via targeting the JMJD3/CLU axis

Nuo Li; Zhifeng Zhao; Pengliang Liu; Yan Zheng; Shuang Cai; Yin Sun; Baoming Wang

Molecular Therapy: Oncolytics (Mar 2021)

Upregulation of deubiquitinase USP7 by transcription factor FOXO6 promotes EC progression via targeting the JMJD3/CLU axis

Nuo Li,
Zhifeng Zhao,
Pengliang Liu,
Yan Zheng,
Shuang Cai,
Yin Sun,
Baoming Wang

Affiliations

Nuo Li: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Zhifeng Zhao: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Pengliang Liu: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Yan Zheng: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Shuang Cai: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Yin Sun: Department of Digestive Endoscopy, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China
Baoming Wang: Interventional Department, The Fourth Hospital of China Medical University, Shenyang 110032, Liaoning Province, P.R. China; Corresponding author: Baoming Wang, Interventional Department, The Fourth Hospital of China Medical University, No. 4, Chongshan East Road, Huanggu District, Shenyang 110032, Liaoning Province, P.R. China.

Journal volume & issue: Vol. 20
pp. 583 – 595

Abstract

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Esophageal carcinoma (EC) is recognized as one of the most frequently occurring malignancies worldwide, and its high morbidity rate motivates efforts to identify potential therapeutic targets. Notably, forkhead box (FOX) family genes are highlighted as possible biomarkers for diagnostics, prognostics, and therapeutics of various malignancies, including EC. Our present study was performed to investigate the underlying mechanism of FOXO6 on the development of EC. We observed a significant upregulation of FOXO6 in EC tissues, contributing to the migration and proliferation in EC cells through gain- and loss-of-function assays. FOXO6 directly interacted with the ubiquitin-specific processing protease 7 (USP7) gene promoter and enhanced its transcriptional activity, which resulted in suppressed cancer cell apoptosis as revealed by chromatin immunoprecipitation (ChIP)-qPCR. USP7 enhanced the ubiquitination of Jumonji domain-containing protein D3 (JMJD3), elevated JMJD3-promoted growth of EC cells, and transcriptionally activated clusterin (CLU) expression at the promoter region via histone H3 lysine 27 tri-methyl (H3K27me3) demethylation, according to immunoprecipitation and ubiquitination assays. Finally, we verified that FOXO6 mediated effects on the USP7/JMJD3/CLU axis to exert an oncogenic role in vivo, which was blocked by USP7 and JMJD3 inhibitor. Our findings demonstrate an important role of the FOXO6/USP7/JMJD3/CLU pathway in EC progression and thus provide attractive potential therapeutic targets for EC patients.

Published in Molecular Therapy: Oncolytics

ISSN: 2372-7705 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: http://www.cell.com/molecular-therapy-family/oncolytics/latest-content

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