组蛋白去乙酰化酶HDAC3调控子宫内膜癌中STING表达的机制研究

Endometrial carcinoma is a malignant tumor of the reproductive system originating from the uterine epithelium. Its incidence is increasing year by year and tends to be younger. For patients who need to retain fertility and who are difficult to treat, there is a lack of effective targeted drugs. Stimulator of interferon genes (STING) is a potential target for the treatment of endometrial carcinoma that activates anti-tumor immunity，but the mechanism of its expression regulation is still unclear. In the previous study, the applicant found that STING expression was down-regulated in endometrial carcinoma， and the analysis of STING promoter revealed that there was a potential binding site of estrogen receptor ERα，in addition, estrogen reduced the expression of STING. ERα has been reported to inhibit gene expression due to histone deacetylase HDAC3. Further study found that HDAC3 inhibitor promoted the expression of STING, and estrogen increased the binding of HDAC3 to ERα. Therefore, applicant proposed the following scientific hypothesis: estrogen-ERα represses STING expression through deacetylation due to HDAC3; specific HDAC3 inhibitor could block this process to alleviate endometrial carcinoma. In this project, we intend to elucidate the molecular mechanism of STING mediated by ERα through HDAC3 using cells, animals and clinical samples. This project will provide theoretical basis and new ideas for the application of HDAC3 inhibitor against endometrial carcinoma targeting STING.

子宫内膜癌是起源于子宫上皮的生殖系统恶性肿瘤，发病率逐年增加并呈年轻化趋势，对需保留生育能力和较难治疗的晚期患者，缺少有效的靶向药物。干扰素刺激基因（STING）激活抗肿瘤免疫是遏制子宫内膜癌的潜在靶点，但其表达调控机制尚不明确。申请者在前期研究中发现子宫内膜癌中STING表达下调，分析STING启动子区发现有雌激素受体ERα潜在结合位点，且雌激素抑制STING的表达。据报道，ERα能通过组蛋白去乙酰化酶HDAC3抑制基因表达。进一步研究发现HDAC3抑制剂促进STING的表达，且雌激素促进HDAC3与ERα的结合。故提出科学假说：雌激素-ERα通过HDAC3异常去乙酰化作用下调STING；HDAC3抑制剂能阻断这一过程抑制子宫内膜癌。本课题拟通过细胞、动物和临床样本阐明ERα通过HDAC3下调STING的分子机制，为HDAC3抑制剂靶向STING抗子宫内膜癌的应用提供理论依据和新思路。

子宫内膜癌是起源于子宫上皮的生殖系统恶性肿瘤，发病率逐年增加并呈年轻化趋势，对 需保留生育能力和较难治疗的晚期患者，缺少有效的靶向药物。干扰素刺激基因(STING)激 活抗肿瘤免疫是遏制子宫内膜癌的潜在靶点，但其表达调控机制尚不明确。雌激素是诱发子宫内膜癌的常见高危因素。本研究目标为探索子宫内膜癌中STING表达抑制的分子机制，分析子宫内膜癌中ERα是否通过HDAC3调控STING表达并进一步分析HDAC3抑制STING表达的分子机制，最终探索HDAC3抑制剂靶向STING治疗子宫内膜癌的可行性。本研究在细胞和小叔层面验证了过表达或激活治疗子宫内膜癌的有效性。对分子机制的研究中发现：蛋白互作分析显示，雌二醇能够有效促进ERα与HDAC3的结合。因此雌激素能够通过受体ERα招募HDAC3，ChIP结果显示HDAC3能够抑制H3K4的乙酰化并结合STING的启动子区从而调控STING启动子活性，抑制STING的表达。促进STING的表达能够有效地抑制子宫内膜癌进程。HDAC3抑制剂能阻断雌激素-ERα-HDAC3-STING这一过程有效得抑制子宫内膜癌，在STING敲除的子宫内膜癌细胞系中，HDAC3抑制剂无法有效抑制子宫内膜癌细胞的增殖促进其凋亡，证明了STING是HDAC3抑制剂治疗子宫内膜癌的关键靶点。本项目从细胞、动物和临床样本等多层次阐述STING表达调控的分子机制，并为分子靶向治疗子宫内膜癌提供了新的思路和研究基础。