Chen Guofang, Yan Qiang, Liu Lin, Wen Xinyue, Zeng Hongliang, Yin Shasha
Shanghai Key Laboratory of Maternal Fetal Medicine, Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
Reproduction, and Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China.
Cancers (Basel). 2022 Sep 28;14(19):4718. doi: 10.3390/cancers14194718.
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.
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 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.
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.
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.
干扰素基因刺激因子（STING）通路在抗肿瘤免疫中起关键作用，且受到多种翻译后修饰的严格调控。然而，STING乙酰化在子宫内膜肿瘤发生调控中的作用仍不清楚。
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，并通过在EC中起关键作用的组蛋白去乙酰化酶（HDAC）探索其表观遗传调控机制。我们使用免疫组化（IHC）和定量逆转录聚合酶链反应（qRT-PCR）检测子宫内膜癌组织中STING表达的蛋白水平和mRNA水平，然后通过细胞计数试剂盒8（CCK8）和流式细胞术探索STING在肿瘤增殖和凋亡中的潜在作用，并通过小鼠异种移植试验确定STING在致瘤性中的作用。我们通过染色质免疫沉淀分析（ChIP）和免疫共沉淀（Co-IP）探索STING调控中乙酰化改变的可能关系，并使用CRISPR-Cas9在ECC1和Ishikawa细胞中敲除HDAC3，以进一步证实HDAC3抑制剂RGFP-966诱导的STING恢复在增殖和凋亡中的关键作用。
我们发现STING表达大幅降低，且是细胞增殖和凋亡的重要调节因子；无论是通过药理学还是遗传学方法激活或过表达STING，在很大程度上都会阻断EC中的细胞增殖并诱导凋亡。此外，STING表达受到β-雌二醇和HDAC3的失调调控。从机制上来说，我们确定HDAC3可与β-雌二醇-雌激素受体α（β-estradiol-ERα）相互作用，并诱导STING启动子处组蛋白3赖氨酸4（histone 3 lysine 4）的去乙酰化，从而降低STING表达。抑制HDAC3可增加STING表达，从而抑制肿瘤发生。
本研究揭示了HDAC3通过β-雌二醇-ERα抑制STING转录的新分子机制，并为对抗子宫内膜癌提供了一种有前景的治疗方法（HDAC和STING联合使用）。
