PMID- 34118928
OWN - NLM
STAT- MEDLINE
DCOM- 20210630
LR  - 20220531
IS  - 1479-5876 (Electronic)
IS  - 1479-5876 (Linking)
VI  - 19
IP  - 1
DP  - 2021 Jun 12
TI  - HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 
      expression through KLF5 deacetylation.
PG  - 258
LID - 10.1186/s12967-021-02812-7 [doi]
LID - 258
AB  - BACKGROUND: Asthma is a frequently occurring respiratory disease with an 
      increasing incidence around the world. Airway inflammation and remodeling are 
      important contributors to the occurrence of asthma. We conducted this study 
      aiming at exploring the effect of Histone deacetylase 4 (HDAC4)-mediated 
      Kruppel-like factor 5 (KLF5)/Slug/CXC chemokine ligand-12 (CXCL12) axis on the 
      development of asthma in regulation of airway inflammation and remodeling. 
      METHODS: An asthmatic rat model was induced by ovalbumin (OVA) irrigation, and 
      determined HDAC4, KLF5, Slug, and CXCL12 expression in the lung tissues by 
      RT-qPCR and Western blot assay. OVA was also used to induce a cell model of 
      asthma in human BEAS-2B and HBE135-E6E7bronchial epithelial cells. The airway 
      hyperresponsiveness (AHR), and expression of inflammatory cytokines in model mice 
      were examined using methacholine challenge test and ELISA. The biological 
      behaviors were measured in asthma model bronchial smooth muscle cells (BSMCs) 
      following loss- and gain- function approaches. The interactions between HDAC4, 
      KLF5, Slug, and CXCL12 were also detected by IP assay, dual luciferase gene 
      reporter assay, and ChIP. RESULTS: HDAC4 was upregulated in lung tissues of 
      OVA-induced asthmatic mice, and inhibition of HDAC4 alleviated the airway 
      inflammation and remodeling. HDAC4 increased KLF5 transcriptional activity 
      through deacetylation; deacetylated KLF5 bound to the promoter of Slug and 
      transcriptionally upregulated Slug expression, which in turn increased the 
      expression of CXCL12 to promote the inflammation in bronchial epithelial cells 
      and thus induce the proliferation and migration of BSMCs. CONCLUSION: 
      Collectively, HDAC4 deacetylates KLF5 to upregulate Slug and CXCL12, thereby 
      causing airway remodeling and facilitating progression of asthma.
FAU - Wei, Wendi
AU  - Wei W
AD  - Department of Hepatology, Taian Hospital of Traditional Chinese Medicine, Taian, 
      271000, People's Republic of China.
FAU - Chen, Weida
AU  - Chen W
AD  - Department of Geriatric Medicine, Affiliated Hospital of Shandong University of 
      Traditional Chinese Medicine, Jinan, 250355, Shandong, People's Republic of 
      China.
FAU - He, Naifeng
AU  - He N
AD  - School of Health, Shandong University of Traditional Chinese Medicine, Jinan, 
      250355, Shandong, People's Republic of China. 944580375@qq.com.
LA  - eng
PT  - Journal Article
DEP - 20210612
PL  - England
TA  - J Transl Med
JT  - Journal of translational medicine
JID - 101190741
RN  - 0 (Chemokines, CXC)
RN  - 0 (Klf5 protein, mouse)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Ligands)
RN  - 0 (Repressor Proteins)
RN  - 9006-59-1 (Ovalbumin)
RN  - EC 3.5.1.98 (HDAC4 protein, human)
RN  - EC 3.5.1.98 (HDAC4 protein, rat)
RN  - EC 3.5.1.98 (Hdac5 protein, mouse)
RN  - EC 3.5.1.98 (Histone Deacetylases)
SB  - IM
MH  - Airway Remodeling
MH  - Animals
MH  - *Asthma/genetics
MH  - Chemokines, CXC
MH  - Disease Models, Animal
MH  - Histone Deacetylases
MH  - Kruppel-Like Transcription Factors/genetics
MH  - Ligands
MH  - Lung
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Ovalbumin
MH  - Rats
MH  - Repressor Proteins
PMC - PMC8199843
OTO - NOTNLM
OT  - Airway remodeling
OT  - Asthma
OT  - CXCL12
OT  - Deacetylation
OT  - HDAC4
OT  - Inflammation
OT  - KLF5
OT  - Slug
OT  - Transcriptional activity
COIS- The authors declare no conflict of interest.
EDAT- 2021/06/14 06:00
MHDA- 2021/07/01 06:00
PMCR- 2021/06/12
CRDT- 2021/06/13 20:22
PHST- 2020/12/10 00:00 [received]
PHST- 2021/04/01 00:00 [accepted]
PHST- 2021/06/13 20:22 [entrez]
PHST- 2021/06/14 06:00 [pubmed]
PHST- 2021/07/01 06:00 [medline]
PHST- 2021/06/12 00:00 [pmc-release]
AID - 10.1186/s12967-021-02812-7 [pii]
AID - 2812 [pii]
AID - 10.1186/s12967-021-02812-7 [doi]
PST - epublish
SO  - J Transl Med. 2021 Jun 12;19(1):258. doi: 10.1186/s12967-021-02812-7.