HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
Open accessAbstract
NAD+-dependent SIRT7 deacylase plays essential roles in ribosome biogenesis, stress response, genome integrity, metabolism and aging, while how it is transcriptionally regulated is still largely unclear. TGF-β signaling is highly conserved in multicellular organisms, regulating cell growth, cancer stemness, migration and invasion. Here, we demonstrate that histone deacetylase HDAC8 forms complex with SMAD3/4 heterotrimer and occupies SIRT7 promoter, wherein it deacetylates H4 and thus suppresses SIRT7 transcription. Treatment with HDAC8 inhibitor compromises TGF-β signaling via SIRT7-SMAD4 axis and consequently, inhibits lung metastasis and improves chemotherapy efficacy in breast cancer. Our data establish a regulatory feedback loop of TGF-β signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-β signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-β signaling related diseases.
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In breast cancer, TGF-β signaling correlates with stemness and metastasis via SMAD3/4 oligomerization.
“In breast cancer, TGF-β signaling correlates with stemness and metastasis via oligomerization of SMAD3/4.”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Tang et al., 2020
SIRT7 is an antagonist of TGF-β signaling by promoting SMAD4 degradation.
“SIRT7, is an important antagonist of the TGF-β signaling, by promoting SMAD4 degradation.(Tang et al., 2020).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Tang et al., 2020
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- [48]Tang M., Li Z., Zhang C., Lu X., Tu B., Cao Z., Li Y., Chen Y., Jiang L., Wang H. et al. SIRT7-mediated ATM deacetylation is essential for its deactivation and DNA damage repair. Sci. Adv. 2019; 5: eaav1118. 30944854 PMC6436926
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Xia, W., Li, M., Jiang, X., Huang, X., Gu, S., Ye, J., Zhu, L., Hou, M., & Zan, T. (2022) · Journal of Nanobiotechnology · doi:10.1186/s12951-022-01348-2 · Cited by 72 · see citing works
HDACs and the epigenetic plasticity of cancer cells: target the complexity
Brancolini, C., Gagliano, T., & Minisini, M. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2022.108190 · Cited by 55 · see citing works
- Authors
- Tang, X., Li, G., Su, F., Cai, Y., Shi, L., Meng, Y., Liu, Z., Sun, J., Wang, M., Qian, M., Wang, Z., Xu, X., Cheng, Y.-X., Zhu, W.-G., & Liu, B.
- Affiliations
- Shenzhen University (CN)
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China
- Corresponding author
- Liu, Baohua
- ORCID
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-01-23
- Volume
- 48
- Issue
- 6
- Pages
- 2912-2923
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC7102950
- OpenAlex
- W3001213098
- Cited by
- 91
- References
- 64
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 20 · 2023: 18 · 2022: 20 · 2021: 9 · 2020: 7
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- National Key Research and Development Program of China (2017YFA0503900)
- National Natural Science Foundation of China (91849208, 81702909, 81972602, 81871114, 81571374, 91949124, 8187051935)
- Science and Technology Program of Guangdong Province in China (2017B030301016, 2019B030301009, 2019A151510472)
- Shenzhen Municipal Commission of Science and Technology Innovation (JCYJ20160226191451487, KQJSCX20180328093403969, JCYJ20180507182044945)
- China Postdoctoral Science Foundation (2015M582419)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- HDAC8, SIRT7, TGF-beta signaling, histone deacetylation, transcriptional repression, lung metastasis, breast cancer, HDAC8 inhibitors, chromatin remodeling, cell migration, chemotherapy efficacy
- MeSH terms
- Cell Movement, Cell Survival, Histone Deacetylases, Humans, Neoplasm Metastasis, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Transcription, Genetic, Signal Transduction, Transforming Growth Factor beta, Drug Resistance, Neoplasm, Sirtuins, Chromatin Assembly and Disassembly, Cell Line, Tumor, Smad3 Protein, Smad4 Protein, HEK293 Cells
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