SIRT7 is an NAD⁺-dependent histone/non-histone deacetylase, which is highly expressed in different types of cancer including thyroid cancer; however, its biological function in thyroid cancer is still undiscovered. In this study, we found that SIRT7 expression was elevated in papillary thyroid cancers (PTCs), and demonstrated that SIRT7 knockdown dramatically inhibited the proliferation, colony formation, migration and invasion of thyroid cancer cells, and induced thyroid cancer cell cycle arrest and apoptosis. Conversely, SIRT7 re-expression markedly enhanced thyroid cancer cell growth, invasiveness and tumorigenic potential in nude mice. Further studies revealed that SIRT7 exerted an oncogenic function in thyroid tumorigenesis by phosphorylation of Akt and p70S6K1. Mechanistically, SIRT7 binds to the promoter of deleted in breast cancer-1 (DBC1), an endogenous inhibitor of SIRT1, and represses its transcription via deacetylation of H3K18Ac. This results in enhanced interactions between SIRT1 and Akt or p70S6K1, thereby promoting deacetylation and subsequent phosphorylation of Akt and p70S6K1 through a SIRT1-dependent manner. Altogether, our results show that DBC1 is a downstream target of SIRT7, and first uncover that SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via the modulation of DBC1/SIRT1 axis.

中文翻译：

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SIRT7通过磷酸化以及通过DBC1 / SIRT1轴激活Akt和p70S6K1来促进甲状腺肿瘤发生。

SIRT7是NAD ⁺依赖的组蛋白/非组蛋白脱乙酰基酶，在不同类型的癌症（包括甲状腺癌）中高表达；然而，其在甲状腺癌中的生物学功能仍未被发现。在这项研究中，我们发现SIRT7的表达在甲状腺乳头状癌（PTC）中升高，并证明SIRT7的抑制显着抑制了甲状腺癌细胞的增殖，集落形成，迁移和侵袭，并诱导了甲状腺癌细胞的周期阻滞和凋亡。相反，SIRT7的重新表达显着增强了裸鼠中甲状腺癌细胞的生长，侵袭性和致瘤性。进一步的研究表明，SIRT7通过Akt和p70S6K1的磷酸化在甲状腺肿瘤发生中发挥致癌作用。从机理上讲，SIRT7与乳腺癌1（DBC1）中的delete的启动子结合，SIRT1的内源性抑制剂，并通过H3K18Ac脱乙酰化抑制其转录。这导致SIRT1与Akt或p70S6K1之间的相互作用增强，从而通过依赖SIRT1的方式促进Akt和p70S6K1的脱乙酰化和随后的磷酸化。总之，我们的结果表明DBC1是SIRT7的下游靶标，并且首先发现SIRT7通过DBC1 / SIRT1轴的调节通过Akt和p70S6K1的磷酸化和激活来促进甲状腺肿瘤发生。