The epigenetic factor CHD4 contributes to metastasis by regulating the EZH2/β-catenin axis and acts as a therapeutic target in ovarian cancer

Journal of Translational Medicine

Research

Huiran Yue¹  Jun Li¹  Jieyu Wang²  Wenzhi Li²  Xin Lu²  Fangfang Zhong³ 

[1] Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 200090, Shanghai, China;Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, 200090, Shanghai, China;Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, 200090, Shanghai, China;Department of Pathology, Obstetrics and Gynecology Hospital, Fudan University, 200090, Shanghai, China;

关键词: Chromodomain-helicase-DNA-binding protein 4;    Ovarian cancer;    Histone deacetylase inhibitor;    Romidepsin;    Metastases;   

DOI  :  10.1186/s12967-022-03854-1

 received in 2022-09-08, accepted in 2022-12-26,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundThe overall survival rate of patients with advanced ovarian cancer (OC) has remained static for several decades. Advanced ovarian cancer is known for its poor prognosis due to extensive metastasis. Epigenetic alterations contribute to tumour progression and therefore are of interest for potential therapeutic strategies.MethodsFollowing our previous study, we identified that CHD4, a chromatin remodelling factor, plays a strong role in ovarian cancer cell metastasis. We investigated the clinical significance of CHD4 through TCGA and GEO database analyses and explored the effect of CHD4 expression modulation and romidepsin treatment on the biological behaviour of ovarian cancer through CCK-8 and transwell assays. Bioluminescence imaging of tumours in xenografted mice was applied to determine the therapeutic effect of romidepsin. GSEA and western blotting were used to screen the regulatory mechanism of CHD4.ResultsIn ovarian cancer patient specimens, high CHD4 expression was associated with a poor prognosis. Loss of function of CHD4 in ovarian cancer cells induced suppression of migration and invasion. Mechanistically, CHD4 knockdown suppressed the expression of EZH2 and the nuclear accumulation of β-catenin. CHD4 also suppressed the metastasis of ovarian cancer cells and prevented disease progression in a mouse model. To inhibit the functions of CHD4 that are mediated by histone deacetylase, we evaluated the effect of the HDAC1/2 selective inhibitor romidepsin. Our findings indicated that treatment with romidepsin suppressed the progression of metastases in vitro and in vivo.ConclusionsCollectively, our results uncovered an oncogenic function of CHD4 in ovarian cancer and provide a rationale for clinical trials of romidepsin in ovarian cancer patients.

【 授权许可】

CC BY   
© The Author(s) 2023

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