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

Author:

Tang Xiaolong12,Li Guo3,Su Fengting12,Cai Yanlin12,Shi Lei12,Meng Yuan12,Liu Zuojun12,Sun Jie12,Wang Ming12,Qian Minxian12,Wang Zimei124,Xu Xingzhi24,Cheng Yong-Xian2,Zhu Wei-Guo24,Liu Baohua1245ORCID

Affiliation:

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

Abstract

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.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Science and Technology Program of Guangdong Province in China

Shenzhen Municipal Commission of Science and Technology Innovation

China Postdoctoral Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Genetics

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