Histone Deacetylase 3 Governs β-Estradiol-ERα-Involved Endometrial Tumorigenesis via Inhibition of STING Transcription.
Histone Deacetylase 3 Governs β-Estradiol-ERα-Involved Endometrial Tumorigenesis via Inhibition of STING Transcription.
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组蛋白去乙酰化酶3通过抑制STING转录调控β-雌二醇- er α-参与的子宫内膜肿瘤发生。
DOI：
10.3390/cancers14194718
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发表时间：
2022-09-28
期刊：
影响因子：
5.2
通讯作者：
Yin, Shasha
中科院分区：
文献类型：
--
作者：
Chen, Guofang;Yan, Qiang;Liu, Lin;Wen, Xinyue;Zeng, Hongliang;Yin, Shasha
子宫内膜癌是对妇女健康威胁最大的妇科恶性肿瘤之一，与之相关的死亡率不断增加，寻找新的有效方法来对抗子宫内膜癌正在成为临床挑战。干扰素基因刺激因子（stimulator of interferon genes，STING）通路在抗肿瘤免疫中起重要作用，受多种翻译后修饰的严格调控。本研究的目的是揭示STING在子宫内膜癌中的表达及其对乙酰化的调控作用。我们证实，STING表达被β-雌二醇和HDAC 3解除调节，并且作为增殖和凋亡的重要调节剂起作用。HDAC 3的抑制增加STING表达，从而抑制肿瘤发生。因此，本研究揭示了HDAC 3通过β-雌二醇-ER α抑制STING转录的一种新的分子机制，并提供了一种有希望的HDAC和STING联合治疗子宫内膜癌的疗法。目的：干扰素基因刺激因子（stimulator of interferon genes，STING）通路在抗肿瘤免疫中起重要作用，受多种翻译后修饰的严格调控。然而，参与STING调节的乙酰化对子宫内膜肿瘤发生的贡献仍不清楚。研究方法：我们试图确定STING在子宫内膜癌（EC）组织和细胞系中的关键作用，并探讨其表观遗传调控机制，HDAC是关键参与EC。采用免疫组化和qRT-PCR检测STING在子宫内膜癌组织中的蛋白表达水平和mRNA表达水平;采用CCK-8和流式细胞术检测STING在子宫内膜癌组织中的表达水平，探讨STING在子宫内膜癌细胞增殖和凋亡中的作用;采用小鼠移植瘤实验检测STING在子宫内膜癌致瘤性中的作用。我们通过ChIP分析和Co-IP探索了乙酰化改变在STING调控中的可能关系，并使用CRISPR-Cas9敲除了ECC 1和石川细胞中的STING，以进一步证实HDAC 3抑制剂RGFP-966诱导的STING恢复在增殖和凋亡中的关键作用。结果如下：我们发现，STING的表达大大降低，并作为一个重要的调节细胞增殖和凋亡;无论是激活或过表达STING，与药理学和遗传学的方法，在很大程度上阻止细胞增殖和诱导细胞凋亡EC。此外，β-雌二醇和HDAC 3均使STING表达失调。在机制上，我们确定HDAC 3可以与β-雌二醇-ER α相互作用，并诱导STING启动子处组蛋白3赖氨酸4的脱乙酰化，从而降低STING表达。HDAC 3的抑制增加STING表达，从而抑制肿瘤发生。结论：这项研究揭示了HDAC 3通过β-雌二醇-ER α抑制STING转录的一种新的分子机制，并为防治子宫内膜癌提供了一种有前途的疗法（HDAC和STING的组合）。
Endometrial carcinoma is one of the most threatening gynecological malignancies to women’s health, with mortality linked to it increasing, and finding novel and effective methods to combat endometrial carcinoma is becoming a clinical challenge. The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. The aim of our study was to uncover the expression and the contribution of acetylation involved in the regulation of STING to endometrial cancer. We confirmed that STING expression was deregulated by both β-estradiol and HDAC3, and worked as an important regulator of proliferation and apoptosis. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Therefore, this study uncovers a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα, and provides a promising therapy with a combination of HDAC and STING for combating endometrial cancer. Purpose: The stimulator of interferon genes (STING) pathway plays a crucial role in antitumor immunity, and it is strictly regulated by many types of post-translational modifications. However, the contribution of acetylation involved in the regulation of STING to endometrial tumorigenesis remains unclear. Methods: We attempted to identify the key role of STING in endometrial carcinoma (EC) tissue and cell lines and explore its epigenetic regulation mechanism by HDACs that are critically involved in EC. We used IHC and qRT-PCR to detect the protein level and mRNA level of STING expression in endometrial carcinoma tissues, then explored the potential role of STING in tumor proliferation and apoptosis by CCK8 and flow cytometry, and identified the STING effect in the tumorigenicity by a mouse xenograft assay. We explored the possible relationship of acetylation alteration in STING regulation by ChIP analysis and Co-IP, and we knocked out STING in ECC1 and Ishikawa cells using CRISPR-Cas9 to further confirm the critical role of STING restoration induced by HDAC3 inhibitor RGFP-966 in the proliferation and apoptosis. Results: We found that STING expression was largely decreased and worked as an important regulator of cell proliferation and apoptosis; either activated or overexpressed STING, with both pharmacological and genetic approaches, largely blocked cell proliferation and induced apoptosis in EC. Moreover, STING expression was deregulated by both β-estradiol and HDAC3. Mechanically, we determined that HDAC3 can interact with β-estradiol-ERα and induce deacetylation of histone 3 lysine 4 at the STING promoter, thereby decreasing STING expression. Inhibition of HDAC3 increased STING expression, thereby inhibiting tumorigenesis. Conclusion: This study reveals a novel molecular mechanism by which HDAC3 inhibits STING transcription via β-estradiol-ERα and provides a promising therapy (a combination of HDAC and STING) for combating endometrial cancer.
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作者：
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影响因子：
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作者：
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DOI：
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发表时间：
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影响因子：
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