Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner.
Hypoxia Increases ATX Expression by Histone Crotonylation in a HIF-2α-Dependent Manner.
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DOI：
10.3390/ijms24087031
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发表时间：
2023-04-11
影响因子：
5.6
通讯作者：
Zhang, Junjie
中科院分区：
文献类型：
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作者：
Qu, Mengxia;Long, Yang;Wang, Yuqin;Yin, Nan;Zhang, Xiaotian;Zhang, Junjie
Autotaxin （ATX）是由溶血磷脂酰胆碱（LPC）生成溶血磷脂酸（LPA）的关键酶，通过ATX-LPA轴参与肿瘤发生，被认为是肿瘤治疗中有价值的靶点。缺氧是实体肿瘤的一个主要特征，并通过基因表达谱的显著改变促进肿瘤的发展。在这里，我们发现在人结肠癌SW480细胞中，缺氧以缺氧诱导因子（HIF） 2α依赖的方式诱导ATX表达。HIF-2α直接与ATX启动子中的特定缺氧反应元件（HREs）结合。在缺氧条件下，敲除或抑制ATX可抑制SW480细胞的迁移，而加入LPA可挽救SW480细胞的迁移，提示缺氧时诱导ATX可通过ATX-LPA轴促进癌细胞迁移。进一步的研究表明，HIF-2α通过募集p300/CBP诱导ATX表达，导致缺氧时ATX启动子区组蛋白H3的巴酮化而非乙酰化。此外，在常氧条件下，细胞组蛋白巴豆酰化水平的升高可诱导ATX的表达。综上所述，我们的研究结果表明，缺氧时，组蛋白巴豆酰化以hif -2α依赖的方式诱导SW480细胞中的ATX，而作为一种新的ATX表达调控机制，组蛋白巴豆酰化上调ATX的表达并不局限于缺氧。
Autotaxin (ATX), the key enzyme that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC), is involved in tumorigenesis through the ATX-LPA axis and is regarded as a valuable target in tumor therapy. Hypoxia is a major feature of solid tumors and contributes to tumor development with striking alterations in the gene expression profile. Here, we show that hypoxia induces ATX expression in a hypoxia-inducible factor (HIF) 2α-dependent fashion in human colon cancer SW480 cells. HIF-2α is directly bound to specific hypoxia response elements (HREs) in the ATX promoter. Under hypoxic conditions, knockout or inhibition of ATX suppressed the migration of SW480 cells, which could be rescued by the addition of LPA, suggesting that the induction of ATX during hypoxia promotes cancer cell migration through the ATX-LPA axis. Further studies showed that ATX expression was induced by HIF-2α through recruiting p300/CBP, which led to crotonylation but not acetylation of histone H3 in the ATX promoter region during hypoxia. Moreover, elevation of cellular histone crotonylation levels could induce ATX expression under normoxic conditions. In conclusion, our findings reveal that ATX is induced in SW480 cells during hypoxia by histone crotonylation in a HIF-2α-dependent manner, while as a novel mechanism of ATX expression regulation, the upregulation of ATX expression by histone crotonylation is not confined to hypoxia.
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DOI：
10.4049/jimmunol.1302831
发表时间：
2014-02-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
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作者：
Knowlden S;Georas SN
通讯作者：
Georas SN
影响因子：
3.9
作者：
Li K;Wang Z
通讯作者：
Wang Z
影响因子：
4.8
作者：
Kishi, Yasuhiro;Okudaira, Shinichi;Arai, Hiroyuki
通讯作者：
Arai, Hiroyuki
影响因子：
4.8
作者：
Hogenesch, JB;Chan, WK;Bradfield, CA
通讯作者：
Bradfield, CA
影响因子：
5.2
作者：
通讯作者：
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