HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
HDAC8 cooperates with SMAD3/4 complex to suppress SIRT7 and promote cell survival and migration
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HDAC8与SMAD3/4复合物配合抑制SIRT7并促进细胞存活和迁移
DOI：
10.1093/nar/gkaa039
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发表时间：
2020-04-06
影响因子：
14.9
通讯作者：
Liu, Baohua
中科院分区：
文献类型：
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作者：
Tang, Xiaolong;Li, Guo;Liu, Baohua
NAD（+）依赖性SIRT 7脱酰酶在核糖体生物合成、应激反应、基因组完整性、代谢和衰老中起着重要作用，但其转录调控机制尚不清楚。TGF-β信号传导在多细胞生物体中高度保守，调节细胞生长、癌症干化、迁移和侵袭。在这里，我们证明了组蛋白脱乙酰酶HDAC 8与SMAD 3/4异源三聚体形成复合物并占据SIRT 7启动子，其中它使H4脱乙酰，从而抑制SIRT 7转录。HDAC 8抑制剂治疗通过SIRT 7-SMAD 4轴损害TGF-β信号传导，因此抑制肺转移并改善乳腺癌的化疗疗效。我们的数据建立了TGF-β信号传导的调节反馈环，其中HDAC 8作为SMAD 3/4复合物的新型辅因子，通过局部染色质重塑转录抑制SIRT 7，从而进一步激活TGF-β信号传导。靶向HDAC 8表现出对TGF-β信号传导相关疾病的治疗潜力。
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-beta 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-beta 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-beta signaling, wherein HDAC8 as a novel cofactor of SMAD3/4 complex, transcriptionally suppresses SIRT7 via local chromatin remodeling and thus further activates TGF-beta signaling. Targeting HDAC8 exhibits therapeutic potential for TGF-beta signaling related diseases.