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表观遗传因子 CHD4 通过调节 EZH2/β-catenin 轴促进转移，是卵巢癌的治疗靶点。

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

机构信息

Department of Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200090, China.

Shanghai Key Laboratory of Female Reproductive Endocrine-Related Disease, Fudan University, Shanghai, 200090, China.

出版信息

J Transl Med. 2023 Jan 21;21(1):38. doi: 10.1186/s12967-022-03854-1.

DOI:10.1186/s12967-022-03854-1
PMID:36681835
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9862813/
Abstract

BACKGROUND

The 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.

METHODS

Following 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.

RESULTS

In 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.

CONCLUSIONS

Collectively, our results uncovered an oncogenic function of CHD4 in ovarian cancer and provide a rationale for clinical trials of romidepsin in ovarian cancer patients.

摘要

背景

几十年来，晚期卵巢癌（OC）患者的总体生存率一直保持稳定。由于广泛转移，晚期卵巢癌预后不良。表观遗传改变促进肿瘤进展，因此是潜在治疗策略的关注点。

方法

在我们之前的研究之后，我们确定了染色质重塑因子 CHD4 在卵巢癌细胞转移中起重要作用。我们通过 TCGA 和 GEO 数据库分析研究了 CHD4 的临床意义，并通过 CCK-8 和 Transwell 测定探索了 CHD4 表达调节和罗米地辛治疗对卵巢癌细胞生物学行为的影响。异种移植小鼠肿瘤的生物发光成像用于确定罗米地辛的治疗效果。GSEA 和 Western blot 用于筛选 CHD4 的调节机制。

结果

在卵巢癌患者标本中，CHD4 高表达与预后不良相关。卵巢癌细胞中 CHD4 的功能丧失诱导迁移和侵袭抑制。在机制上，CHD4 敲低抑制了 EZH2 的表达和 β-连环蛋白的核积累。CHD4 还抑制了卵巢癌细胞的转移，并在小鼠模型中防止了疾病进展。为了抑制由组蛋白去乙酰化酶介导的 CHD4 功能，我们评估了 HDAC1/2 选择性抑制剂罗米地辛的作用。我们的研究结果表明，罗米地辛治疗在体外和体内均抑制转移进展。

结论

总之，我们的研究结果揭示了 CHD4 在卵巢癌中的致癌功能，并为在卵巢癌患者中进行罗米地辛临床试验提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/e9727b456412/12967_2022_3854_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/7715c80e5f48/12967_2022_3854_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/c8be82bcac6f/12967_2022_3854_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/72f729dcc559/12967_2022_3854_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/cb5bb8a6fca0/12967_2022_3854_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/3f91bcdcf6d4/12967_2022_3854_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/4fc40228969d/12967_2022_3854_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/e9727b456412/12967_2022_3854_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/7715c80e5f48/12967_2022_3854_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/c8be82bcac6f/12967_2022_3854_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/72f729dcc559/12967_2022_3854_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/cb5bb8a6fca0/12967_2022_3854_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/3f91bcdcf6d4/12967_2022_3854_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/4fc40228969d/12967_2022_3854_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2192/9862813/e9727b456412/12967_2022_3854_Fig7_HTML.jpg

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