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; Hyun Kook

doi:10.1038/ncomms10492

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

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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.

Original language	English
Article number	10492
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms10492
State	Published - 1 Feb 2016

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Kwon, D. H., Eom, G. H., Ko, J. H., Shin, S., Joung, H., Choe, N., Nam, Y. S., Min, H. K., Kook, T., Yoon, S., Kang, W., Kim, Y. S., Kim, H. S., Choi, H., Koh, J. T., Kim, N., Ahn, Y., Cho, H. J., Lee, I. K., ... Kook, H. (2016). MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification. Nature Communications, 7, Article 10492. https://doi.org/10.1038/ncomms10492

@article{11feb1c624be46f5b8d51571baf4c1be,

title = "MDM2 E3 ligase-mediated ubiquitination and degradation of HDAC1 in vascular calcification",

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.",

author = "Kwon, {Duk Hwa} and Eom, {Gwang Hyeon} and Ko, {Jeong Hyeon} and Sera Shin and Hosouk Joung and Nakwon Choe and Nam, {Yoon Seok} and Min, {Hyun Ki} and Taewon Kook and Somy Yoon and Wanseok Kang and Kim, {Yong Sook} and Kim, {Hyung Seok} and Hyuck Choi and Koh, {Jeong Tae} and Nacksung Kim and Youngkeun Ahn and Cho, {Hyun Jai} and Lee, {In Kyu} and Park, {Dong Ho} and Kyoungho Suk and Seo, {Sang Beom} and Wissing, {Erin R.} and Mendrysa, {Susan M.} and Nam, {Kwang Il} and Hyun Kook",

year = "2016",

month = feb,

day = "1",

doi = "10.1038/ncomms10492",

language = "English",

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journal = "Nature Communications",

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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

TY - JOUR

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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U2 - 10.1038/ncomms10492

DO - 10.1038/ncomms10492

M3 - Article

C2 - 26832969

AN - SCOPUS:84956631216

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 10492

ER -

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

Abstract

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