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Cited by 52Histone Deacetylase Inhibitors ResearchAutophagy in Disease and TherapyGastric Cancer Management and Outcomes

HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3

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Zang, Wei-Jie, Hu, Yi-Lin, Qian, Chen-Yu, Feng, Ying, Liu, Jia-Zhou, Yang, Jun-Ling, Huang, Hua, Zhu, Yi-Zhun +1 more·2022·British Journal of Cancer
DOI 10.1038/s41416-022-01805-7PMC PMC9296555
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Abstract

Background: Histone deacetylases (HDACs) have been shown to be involved in tumorigenesis, but their precise role and molecular mechanisms in gastric cancer (GC) have not yet been fully elucidated. Methods: Bioinformatics screening analysis, qRT-PCR, and immunohistochemistry (IHC) were used to identify the expression of HDAC4 in GC. In vitro and in vivo functional assays illustrated the biological function of HDAC4. RNA-seq, GSEA pathway analysis, and western blot revealed that HDAC4 activated p38 MAPK signalling. Immunofluorescence, western blot, and IHC verified the effect of HDAC4 on autophagy. ChIP and dual-luciferase reporter assays demonstrated that the transcriptional regulation mechanism of HDAC4 and ATG4B. Results: HDAC4 is upregulated in GC and correlates with poor prognosis. In vitro and in vivo assays showed that HDAC4 contributes to the malignant phenotype of GC cells. HDAC4 inhibited the MEF2A-driven transcription of ATG4B and prevented MEKK3 from p62-dependent autophagic degradation, thus activating p38 MAPK signalling. Reciprocally, the downstream transcription factor USF1 enhanced HDAC4 expression by regulating HDAC4 promoter activity, forming a positive feedback loop and continuously stimulating HDAC4 expression and p38 MAPK signalling activation. Conclusion: HDAC4 plays an oncogenic role in GC, and HDAC4-based targeted therapy would represent a novel strategy for GC treatment.

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Cited by

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Authors
Zang, W.-J., Hu, Y.-L., Qian, C.-Y., Feng, Y., Liu, J.-Z., Yang, J.-L., Huang, H., Zhu, Y.-Z., & Xue, W.-J.
Affiliations
  • Nantong University (CN)
  • Affiliated Hospital of Nantong University (CN)
  • Macau University of Science and Technology (MO)
Corresponding author
Zhu, Yi-Zhun
ORCID
Venue
British Journal of Cancer
Publisher
Springer Science and Business Media LLC
Published
2022-05-30
Volume
127
Issue
2
Pages
237-248
ISSN
  • 0007-0920 (ISSN-L)
  • 1532-1827
DOI
10.1038/s41416-022-01805-7
PMC
PMC9296555
OpenAlex
W4282050722
Cited by
52
References
0
Citations by year
2026: 7 · 2025: 10 · 2024: 22 · 2023: 11 · 2022: 2
FWCI
3.67
Type
journal article
Language
en
Open access
Licence
Locations
  • British Journal of Cancer (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81672409)
  • Government of Jiangsu Province
  • Nantong Science and Technology Bureau (MS12019026, MSZ19204)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
HDAC4, gastric cancer, MEKK3, autophagic degradation, p38 MAPK signalling, ATG4B, MEF2A, USF1, p62, autophagy, tumor growth, metastasis, histone deacetylase, oncogenic transcriptional regulation
MeSH terms
Autophagy, Histone Deacetylases, Humans, Repressor Proteins, Stomach Neoplasms, MicroRNAs, Cell Line, Tumor, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinase 3, Cell Proliferation, Carcinogenesis

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