HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration

  • Nucleic Acids Res. 2020 Apr 6;48(6):2912-2923. doi: 10.1093/nar/gkaa039.
Xiaolong Tang  1  2 ,  Guo Li  3 ,  Fengting Su  1  2 ,  Yanlin Cai  1  2 ,  Lei Shi  1  2 ,  Yuan Meng  1  2 ,  Zuojun Liu  1  2 ,  Jie Sun  1  2 ,  Ming Wang  1  2 ,  Minxian Qian  1  2 ,  Zimei Wang  1  2  4 ,  Xingzhi Xu  2  4 ,  Yong-Xian Cheng  2 ,  Wei-Guo Zhu  2  4 ,  Baohua Liu  1  2  4  5
Affiliations
  • 1. Shenzhen Key Laboratory for Systemic Aging and Intervention, National Engineering Research Center for Biotechnology (Shenzhen), Medical Research Center, Shenzhen University, Shenzhen 518055, China.
  • 2. Guangdong Key Laboratory for Genome Stability and Human Disease Prevention, Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen 518055, China.
  • 3. Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China.
  • 4. Carson International Cancer Center, Shenzhen University Health Science Center, Shenzhen 518055, China.
  • 5. Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, School of Basic Medical Sciences, Shenzhen University Health Science Center, Shenzhen 518055, China.
PMID: 31970414 DOI: 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.

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