HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
Xiaolong Tang, Li Guo, Fengting Su, Yanlin Cai, Lei Shi, Meng Yuan, Zuojun Liu, Jie Sun, Ming Wang, Minxian Qian, Zimei Wang, Xingzhi Xu, Yong‐Xian Cheng, Wei‐Guo Zhu, Baohua Liu
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.