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.

中文翻译：

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HDAC8与SMAD3 / 4复合物协同抑制SIRT7并促进细胞存活和迁移。

依赖NAD +的SIRT7脱酰基酶在核糖体的生物发生，应激反应，基因组完整性，代谢和衰老中起着至关重要的作用，但是在转录调控方面如何仍不清楚。TGF-β信号在多细胞生物中高度保守，可调节细胞生长，癌干，迁移和侵袭。在这里，我们证明组蛋白脱乙酰基酶HDAC8与SMAD3 / 4异源三聚体形成复合物并占据SIRT7启动子，其中它使H4脱乙酰基并因此抑制SIRT7转录。使用HDAC8抑制剂的治疗会通过SIRT7-SMAD4轴破坏TGF-β信号传导，因此，抑制肺转移并提高乳腺癌的化疗疗效。我们的数据建立了TGF-β信号的调节反馈回路，其中HDAC8作为SMAD3 / 4复合物的新辅助因子，转录通过局部染色质重塑抑制SIRT7，从而进一步激活TGF-β信号传导。靶向HDAC8表现出对TGF-β信号传导相关疾病的治疗潜力。