1 College of Life and Health Sciences, Northeastern University ; The First Affiliated Hospital, Institute of Translational Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Public Health, School of Medicine, Zhejiang University , Hangzhou, China .
2 Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University , Zhengzhou, China .
Antioxid Redox Signal. 2018 May 1;28(13):1224-1237. doi: 10.1089/ars.2017.7161. Epub 2017 Dec 13.
Iron-overload disorders are common and could lead to significant morbidity and mortality worldwide. Due to limited treatment options, there is a great need to develop novel strategies to remove the excess body iron. To discover potential epigenetic modulator in hepcidin upregulation and subsequently decreasing iron burden, we performed an epigenetic screen. The in vivo effects of the identified compounds were further tested in iron-overload mouse models, including Hfe, Hjv, and hepatocyte-specific Smad4 knockout (Smad4;Alb-Cre) mice.
Entinostat (MS-275), the clinical used histone deacetylase 1 (HDAC1) inhibitor, was identified the most potent hepcidin agonist. Consistently, Hdac1-deficient mice also presented higher hepcidin levels than wild-type controls. Notably, the long-term treatment with entinostat in Hfe mice significantly alleviated iron overload through upregulating hepcidin transcription. In contrast, entinostat showed no effect on hepcidin expression and iron levels in Smad4;Alb-Cre mice. Further mechanistic studies revealed that HDAC1 suppressed expression of hepcidin through interacting with SMAD4 rather than deacetylation of SMAD4 or histone-H3 on the hepcidin promoter.
The findings uncovered HDAC1 as a novel hepcidin suppressor through complexing with SMAD4 but not deacetylation of either histone 3 or SMAD4. In addition, our study suggested a novel implication of entinostat in treating iron-overload disorders.
Based on our results, we conclude that entinostat strongly activated hepcidin in vivo and in vitro. HDAC1 could serve as a novel hepcidin suppressor by binding to SMAD4, effect of which is independent of BMP/SMAD1/5/8 signaling. Antioxid. Redox Signal. 28, 1224-1237.
铁过载疾病很常见，可能会导致全球范围内的重大发病率和死亡率。由于治疗选择有限，因此非常需要开发新的策略来去除多余的体内铁。为了发现铁调素上调和随后降低铁负荷的潜在表观遗传调节剂，我们进行了表观遗传筛选。所鉴定的化合物的体内作用进一步在铁过载小鼠模型中进行了测试，包括 Hfe、Hjv 和肝细胞特异性 Smad4 敲除（Smad4;Alb-Cre）小鼠。
恩替诺特（MS-275），一种临床使用的组蛋白去乙酰化酶 1（HDAC1）抑制剂，被鉴定为最有效的铁调素激动剂。一致地，Hdac1 缺陷小鼠的铁调素水平也高于野生型对照。值得注意的是，恩替诺特在 Hfe 小鼠中的长期治疗通过上调铁调素转录显著缓解了铁过载。相比之下，恩替诺特对 Smad4;Alb-Cre 小鼠的铁调素表达和铁水平没有影响。进一步的机制研究表明，HDAC1 通过与 SMAD4 相互作用而不是通过去乙酰化 SMAD4 或组蛋白 H3 来抑制铁调素的表达。
该研究发现 HDAC1 通过与 SMAD4 复合而不是通过去乙酰化组蛋白 3 或 SMAD4 来抑制铁调素的表达，从而成为一种新型铁调素抑制剂。此外，我们的研究表明恩替诺特在治疗铁过载疾病方面具有新的意义。
基于我们的结果，我们得出结论，恩替诺特在体内和体外强烈激活铁调素。HDAC1 可以通过与 SMAD4 结合作为一种新型铁调素抑制剂，其作用不依赖于 BMP/SMAD1/5/8 信号通路。抗氧化。氧化还原信号。28,1224-1237。
