HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
Open Access
- 23 January 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (6), 2912-2923
- https://doi.org/10.1093/nar/gkaa039
Abstract
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.Keywords
Funding Information
- 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)
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