KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC
KAT5 promotes invasion and metastasis through C-MYC stabilization in ATC
复制标题
KAT5 通过 ATC 中的 C-MYC 稳定促进侵袭和转移
DOI：
10.1530/erc-18-0193
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发表时间：
2019-01-01
影响因子：
3.9
通讯作者：
Xu, Bo
中科院分区：
文献类型：
--
作者：
Wei, Xi;Cai, Shang;Xu, Bo
甲状腺未分化癌（ATC）是一种侵袭性癌症，临床预后较差。然而，驱动 ATC 攻击性的机制尚不清楚。 DNA 损伤反应 (DDR) 的组成部分经常在 ATC 中发现突变或异常表达。本研究的目的是利用临床、体外和体内模型建立组蛋白乙酰转移酶赖氨酸 (K) 乙酰转移酶 5（KAT5，一种关键的 DDR 蛋白）与 ATC 侵袭性之间的功能联系。我们通过免疫组织化学分析了 KAT5 的表达，并评估了其与 82 名 ATC 患者的转移和总生存期的关系。使用细胞模型，我们建立了 KAT5 表达和 C-MYC 稳定性的功能联系。然后我们研究了转基因KAT5表达对裸鼠ATC转移的影响。在临床样本中，KAT5表达与ATC转移（P = 0.0009）和总生存率（P = 0.0017）有很强的相关性。在细胞水平上，KAT5的上调显着促进甲状腺癌细胞的增殖和侵袭。我们还发现 KAT5 通过抑制泛素介导的降解来增强 C-MYC 蛋白水平。进一步的证据表明 KAT5 乙酰化并稳定 C-MYC。最后，我们证明改变的 KAT5 表达会影响体内 ATC 肺转移。 KAT5 通过稳定 C-MYC 促进 ATC 侵袭和转移，证明其是 ATC 的新生物标志物和治疗靶点。
Anaplastic thyroid cancer (ATC) is an aggressive cancer with poor clinical prognosis. However, mechanisms driving ATC aggressiveness is not well known. Components of the DNA damage response (DDR) are frequently found mutated or aberrantly expressed in ATC. The goal of this study is to establish the functional link between histone acetyltransferase lysine (K) acetyltransferase 5 (KAT5, a critical DDR protein) and ATC invasiveness using clinical, in vitro and in vivo models. We analyzed the expression of KAT5 by immunohistochemistry and assessed its relationship with metastasis and overall survival in 82 ATC patients. Using cellular models, we established functional connection of KAT5 expression and C-MYC stabilization. We then studied the impact of genetically modified KAT5 expression on ATC metastasis in nude mice. In clinical samples, there is a strong correlation of KAT5 expression with ATC metastasis (P = 0.0009) and overall survival (P = 0.0017). At the cellular level, upregulation of KAT5 significantly promotes thyroid cancer cell proliferation and invasion. We also find that KAT5 enhances the C-MYC protein level by inhibiting ubiquitin-mediated degradation. Further evidence reveals that KAT5 acetylates and stabilizes C-MYC. Finally, we prove that altered KAT5 expression influences ATC lung metastases in vivo. KAT5 promotes ATC invasion and metastases through stabilization of C-MYC, demonstrating it as a new biomarker and therapeutic target for ATC.