Xiangju Yin1,2,3, Qian Wu1,2, Jitender Monga1, Enjun Xie1, Hao Wang1,2, Shufen Wang1, Huizhen Zhang2, Zhan-You Wang1, Tianhua Zhou1, Yujun Shi4, Jack Rogers5, Hening Lin6, Junxia Min1, Fudi Wang1,2. 1. 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. 2 Department of Nutrition, Precision Nutrition Innovation Center, School of Public Health, Zhengzhou University , Zhengzhou, China . 3. 3 Institute of Resources and Environment, Henan Polytechnic University , Jiaozuo, China . 4. 4 Laboratory of Pathology, West China Hospital, Sichuan University , Chengdu, China . 5. 5 Neurochemistry Laboratory, Departments of Psychiatry and Pediatrics, Massachusetts General Hospital and Harvard Medical School , Charlestown, Massachusetts. 6. 6 Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Cornell University , Ithaca, New York.
Abstract
AIMS: 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 (Smad4fl/fl;Alb-Cre+) mice. RESULTS: 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 Smad4fl/fl;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. INNOVATION: 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. CONCLUSIONS: 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.
AIMS: 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 (Smad4fl/fl;Alb-Cre+) mice. RESULTS: Entinostat (MS-275), the clinical used histone deacetylase 1 (HDAC1) inhibitor, was identified the most potent hepcidin agonist. Consistently, Hdac1-deficientmice 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 Smad4fl/fl;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. INNOVATION: 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. CONCLUSIONS: 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.
Entities:
Keywords:
HDAC1 inhibitors; Hfe; Smad4; hepcidin; iron overload