MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification

Duk-Hwa Kwon, Gwang Hyeon Eom, Jeong Hyeon Ko, Sera Shin, Hosouk Joung, Nakwon Choe, Yoon Seok Nam, Hyun-Ki Min, Taewon Kook, Somy Yoon, Wanseok Kang, Yong Sook Kim, Hyung Seok Kim, Hyuck Choi, Jeong-Tae Koh, Nacksung Kim, Youngkeun Ahn, Hyun-Jai Cho, In-Kyu Lee, Dong Ho Park, Kyoungho Suk, Sang Beom Seo, Erin R. Wissing, Susan M. Mendrysa, Kwang-Il Nam and Hyun Kook ()
Additional contact information
Duk-Hwa Kwon: Chonnam National University Medical School
Gwang Hyeon Eom: Chonnam National University Medical School
Jeong Hyeon Ko: Chonnam National University Medical School
Sera Shin: Chonnam National University Medical School
Hosouk Joung: Chonnam National University Medical School
Nakwon Choe: Chonnam National University Medical School
Yoon Seok Nam: Chonnam National University Medical School
Hyun-Ki Min: Chonnam National University Medical School
Taewon Kook: Chonnam National University Medical School
Somy Yoon: Chonnam National University Medical School
Wanseok Kang: Chonnam University Hospital
Yong Sook Kim: Chonnam University Hospital
Hyung Seok Kim: Chonnam National University Medical School
Hyuck Choi: Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University
Jeong-Tae Koh: Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University
Nacksung Kim: Chonnam National University Medical School
Youngkeun Ahn: Chonnam University Hospital
Hyun-Jai Cho: Seoul National University Hospital
In-Kyu Lee: Kyungpook National University School of Medicine
Dong Ho Park: Kyungpook National University School of Medicine
Kyoungho Suk: Brain Science & Engineering Institute, Kyungpook National University School of Medicine
Sang Beom Seo: Chung-Ang University
Erin R. Wissing: College of Veterinary Medicine, Purdue University
Susan M. Mendrysa: College of Veterinary Medicine, Purdue University
Kwang-Il Nam: Chonnam National University Medical School
Hyun Kook: Chonnam National University Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.

Date: 2016
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DOI: 10.1038/ncomms10492

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