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 ParkKyoungho Suk, Sang Beom Seo, Erin R. Wissing, Susan M. Mendrysa, Kwang Il Nam, Hyun Kook

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish
Article number10492
JournalNature Communications
Volume7
DOIs
StatePublished - 1 Feb 2016

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Histone Deacetylase 1
Vascular Calcification
calcification
Ubiquitin-Protein Ligases
Ubiquitination
degradation
Degradation
inhibitors
metabolic diseases
Ablation
Metabolic Diseases
decoys
Animals
Coronary Vessels
arteries
Cardiovascular Diseases
Animal Models
ablation
peptides
Messenger RNA

Cite this

Kwon, D. H., Eom, G. H., Ko, J. H., Shin, S., Joung, H., Choe, N., ... Kook, H. (2016). MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification. Nature Communications, 7, [10492]. https://doi.org/10.1038/ncomms10492
Kwon, Duk Hwa ; Eom, Gwang Hyeon ; Ko, Jeong Hyeon ; Shin, Sera ; Joung, Hosouk ; Choe, Nakwon ; Nam, Yoon Seok ; Min, Hyun Ki ; Kook, Taewon ; Yoon, Somy ; Kang, Wanseok ; Kim, Yong Sook ; Kim, Hyung Seok ; Choi, Hyuck ; Koh, Jeong Tae ; Kim, Nacksung ; Ahn, Youngkeun ; Cho, Hyun Jai ; Lee, In Kyu ; Park, Dong Ho ; Suk, Kyoungho ; Seo, Sang Beom ; Wissing, Erin R. ; Mendrysa, Susan M. ; Nam, Kwang Il ; Kook, Hyun. / MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification. In: Nature Communications. 2016 ; Vol. 7.
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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.",
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Kwon, DH, Eom, GH, Ko, JH, Shin, S, Joung, H, Choe, N, Nam, YS, Min, HK, Kook, T, Yoon, S, Kang, W, Kim, YS, Kim, HS, Choi, H, Koh, JT, Kim, N, Ahn, Y, Cho, HJ, Lee, IK, Park, DH, Suk, K, Seo, SB, Wissing, ER, Mendrysa, SM, Nam, KI & Kook, H 2016, 'MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification', Nature Communications, vol. 7, 10492. https://doi.org/10.1038/ncomms10492

MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification. / Kwon, Duk Hwa; Eom, Gwang Hyeon; Ko, Jeong Hyeon; Shin, Sera; Joung, Hosouk; Choe, Nakwon; Nam, Yoon Seok; Min, Hyun Ki; Kook, Taewon; Yoon, Somy; Kang, Wanseok; Kim, Yong Sook; Kim, Hyung Seok; Choi, Hyuck; Koh, Jeong Tae; Kim, Nacksung; Ahn, Youngkeun; Cho, Hyun Jai; Lee, In Kyu; Park, Dong Ho; Suk, Kyoungho; Seo, Sang Beom; Wissing, Erin R.; Mendrysa, Susan M.; Nam, Kwang Il; Kook, Hyun.

In: Nature Communications, Vol. 7, 10492, 01.02.2016.

Research output: Contribution to journalArticle

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T1 - MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification

AU - Kwon, Duk Hwa

AU - Eom, Gwang Hyeon

AU - Ko, Jeong Hyeon

AU - Shin, Sera

AU - Joung, Hosouk

AU - Choe, Nakwon

AU - Nam, Yoon Seok

AU - Min, Hyun Ki

AU - Kook, Taewon

AU - Yoon, Somy

AU - Kang, Wanseok

AU - Kim, Yong Sook

AU - Kim, Hyung Seok

AU - Choi, Hyuck

AU - Koh, Jeong Tae

AU - Kim, Nacksung

AU - Ahn, Youngkeun

AU - Cho, Hyun Jai

AU - Lee, In Kyu

AU - Park, Dong Ho

AU - Suk, Kyoungho

AU - Seo, Sang Beom

AU - Wissing, Erin R.

AU - Mendrysa, Susan M.

AU - Nam, Kwang Il

AU - Kook, Hyun

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

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