PMID- 36263180
OWN - NLM
STAT- MEDLINE
DCOM- 20221024
LR  - 20230111
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 18
IP  - 15
DP  - 2022
TI  - HDAC5-mediated Smad7 silencing through MEF2A is critical for fibroblast 
      activation and hypertrophic scar formation.
PG  - 5724-5739
LID - 10.7150/ijbs.76140 [doi]
AB  - Transforming growth factor-beta (TGF-beta) signaling plays a key role in excessive 
      fibrosis. As a class IIa family histone deacetylase (HDAC), HDAC5 shows a close 
      relationship with TGF-beta signaling and fibrosis. However, the effect and 
      regulatory mechanism of HDAC5 in hypertrophic scar (HS) formation remain elusive. 
      We show that HDAC5 was overexpressed in HS tissues and depletion of HDAC5 
      attenuated HS formation in vivo and inhibited fibroblast activation in vitro. 
      HDAC5 knockdown (KD) significantly downregulated TGF-beta1 induced Smad2/3 
      phosphorylation and increased Smad7 expression. Meanwhile, Smad7 KD rescued the 
      Smad2/3 phosphorylation downregulation and scar hyperplasia inhibition mediated 
      by HDAC5 deficiency. Luciferase reporter assays and ChIP-qPCR assays revealed 
      that HDAC5 interacts with myocyte enhancer factor 2A (MEF2A) suppressing MEF2A 
      binding to the Smad7 promoter region, which results in Smad7 promoter activity 
      repression. HDAC4/5 inhibitor, LMK235, significantly alleviated hypertrophic scar 
      formation. Our study provides clues for the development of HDAC5 targeting 
      strategies for the therapy or prophylaxis of fibrotic diseases.
CI  - (c) The author(s).
FAU - Gao, Ya
AU  - Gao Y
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Liu, Yangdan
AU  - Liu Y
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Zheng, Danning
AU  - Zheng D
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Ho, Chiakang
AU  - Ho C
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Wen, Dongsheng
AU  - Wen D
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Sun, Jiaming
AU  - Sun J
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Huang, Lu
AU  - Huang L
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Liu, Yuxin
AU  - Liu Y
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Li, Qingfeng
AU  - Li Q
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
FAU - Zhang, Yifan
AU  - Zhang Y
AD  - Department of Plastic & Reconstructive Surgery, Shanghai Ninth People's Hospital, 
      School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220911
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - EC 3.5.1.98 (HDAC5 protein, human)
RN  - EC 3.5.1.98 (Histone Deacetylases)
RN  - EC 1.13.12.- (Luciferases)
RN  - 0 (MEF2 Transcription Factors)
RN  - 0 (MEF2A protein, human)
RN  - 0 (Smad7 Protein)
RN  - 0 (SMAD7 protein, human)
RN  - 0 (Transforming Growth Factor beta)
RN  - 76057-06-2 (Transforming Growth Factors)
SB  - IM
MH  - Humans
MH  - *Cicatrix, Hypertrophic/genetics/metabolism
MH  - Fibroblasts/metabolism
MH  - Fibrosis
MH  - *Histone Deacetylases/metabolism
MH  - Luciferases/metabolism
MH  - *MEF2 Transcription Factors/metabolism
MH  - *Smad7 Protein/metabolism
MH  - Transforming Growth Factor beta/metabolism
MH  - Transforming Growth Factors/metabolism
PMC - PMC9576526
OTO - NOTNLM
OT  - HDAC5
OT  - Hypertrophic scar
OT  - MEF2A
OT  - Smad7
OT  - TGF-beta
COIS- Competing Interests: The authors have declared that no competing interest exists.
EDAT- 2022/10/21 06:00
MHDA- 2022/10/22 06:00
PMCR- 2022/01/01
CRDT- 2022/10/20 02:57
PHST- 2022/06/14 00:00 [received]
PHST- 2022/08/25 00:00 [accepted]
PHST- 2022/10/20 02:57 [entrez]
PHST- 2022/10/21 06:00 [pubmed]
PHST- 2022/10/22 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - ijbsv18p5724 [pii]
AID - 10.7150/ijbs.76140 [doi]
PST - epublish
SO  - Int J Biol Sci. 2022 Sep 11;18(15):5724-5739. doi: 10.7150/ijbs.76140. 
      eCollection 2022.