Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1 α
Monomethyltransferase SETD8 regulates breast cancer metabolism via stabilizing hypoxia-inducible factor 1 α
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DOI：
10.1016/j.canlet.2016.12.038
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发表时间：
2017-04-01
期刊：
影响因子：
9.7
通讯作者：
Zheng, Qi
中科院分区：
文献类型：
--
作者：
Huang, Run;Yu, Yang;Zheng, Qi
SETD8 是一种甲基转移酶，特异性催化组蛋白 H4 上的 20 位赖氨酸单甲基化。先前的研究表明 SETD8 与适当的细胞周期进程、DNA 损伤反应和转录调控相关。最近的一项研究表明，SETD8 在上皮间质转化 (EMT) 中发挥重要作用，与 TWIST 相关并增强乳腺癌细胞的转移潜力。然而，SETD8 对代谢重编程（癌症的标志之一）的贡献从未有过报道。在这项研究中，我们报告 SETD8 是合成代谢的正调节因子。 SETD8 通过缺氧诱导因子 Ia (HIF1 α) 介导的过程重新编程乳腺癌细胞代谢。机制研究表明 SETD8 通过转录后调节稳定 HIF1 α 蛋白水平。此外，我们证明 SETD8 是 HIF1 α 转录靶标。在临床乳腺癌患者组织中，我们观察到 SETD8 与 HIFI% 和 HIF1 α 靶基因呈正相关。总而言之，我们验证了 SETD8 作为一种新型代谢重编程调节剂，并且我们的机制研究揭示了 SETD8 在乳腺癌恶性特性维持中的新功能。 (C) 2017 Elsevier B.V. 保留所有权利。
SETD8 is a methyltransferase that specifically catalyzes the monomethylation of lysine 20 on histone H4. Previous studies have demonstrated that SETD8 is associated with proper cell cycle progression, DNA damage response, and transcriptional regulation. A recent study revealed that SETD8 played an important role in epithelial mesenchymal transition (EMT) in association with TWIST and enhanced metastatic potential of breast cancer cells. However, the contribution of SETD8 to metabolism reprogramming, one hallmark of cancer, has never been reported. In this study, we report that SETD8 was a positive regulator of anabolic metabolism. SETD8 reprograms breast cancer cell metabolism through hypoxiainducible factor la (HIF1 alpha) mediated process. Mechanistic studies indicated that SETD8 stabilized HIF1 alpha protein level through post-transcriptional regulation. Moreover, we demonstrated that SETD8 was a HIF1 alpha transcription target. In clinical breast cancer patient tissues, we observed a positive correlation of SETD8 with HIFI% and HIF1 alpha target genes. Taken together, we validated SETD8 as a novel metabolic reprogramming regulator, and our mechanistic studies shed light on a novel function of SETD8 in breast cancer malignant properties maintenance. (C) 2017 Elsevier B.V. All rights reserved.