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KDM4B Down-Regulates ERα Signaling Independent on its Demethylase Activity in Vascular Calcification
41 Pages Posted: 16 Jun 2023
More...Abstract
Background: Vascular Calcification (VC) is recognized as an independent predictor of cardiovascular events. Estrogen replacement was reported as protective treatment against vascular calcification in postmenopausal women, while it is controversial because of its potential carcinogenicity. ERα co-regulators have been putatively considered as potential therapeutic targets for ERα-related cancers. However, the modulation of ERα action and biological function of ERα co-regulators in vascular calcification are still elusive.
Methods: Quantitative real-time PCR, western blot were performed to detect gene expression. Luciferase reporter assay, Co-immunoprecipitation (Co-IP) and Chromatin immunoprecipitation was performed to detect possible mechanisms. Alizarin Red staining and Quantification of calcium deposition were performed to gene expression.
Findings: KDM4B (Histone lysine demethylases 4B) was identified to be highly expressed in β-phosphoglycerol treated aortic smooth muscle cells (ASMCs) and VitD3-overloaded mice during calcification. KDM4B downregulated ERa-induced transactivation independent of its demethylase activity; KDM4B associated with PRC2 (Polycomb repressive complex 2) complex and ERa. KDM4B depletion decreased the recruitment of PRC complex to estrogen response element (ERE) regions, thereby down-regulating the level of H3K27me3. Finally, KDM4B-mediated enhancement of ASMCs calcification was attenuated by the estrogen treatment, which suggested KDM4B acts as a new potential therapeutic target for VC.
Funding: This study was supported by the National Natural Science Foundation of China (32170603, 31871286 for Yue Zhao, 82273123 for Chunyu Wang, 32100440 for Ge Sun); Liaoning Provincial Project of Applied Basic Research (2022JH2/101300061 for Wen Tian); China Postdoctoral Science Foundation (276066) for Ge Sun; Foundation of Liaoning Province of China (LJKZ0756 for Shengli Wang); Local projects supported by the central government (2022JH6/100100035 for Yue Zhao); Foreign expert project of Ministry of Science and Technology (G2022006007L for Yue Zhao).
Declaration of Interest: The authors have no relevant competing interests to declare in relation to this manuscript.
Ethical Approval: All experiments were approved by the Institutional Animal Protection and Use Committee (IACUC) of China Medical University and performed in accordance with IACUC guidelines.
Keywords: KDM4B, ERα, PRC2, epigenetic regulation, vascular calcification
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