KDM4A regulates HIF-1 levels through H3K9me3.
KDM4A regulates HIF-1 levels through H3K9me3.
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DOI：
10.1038/s41598-017-11658-3
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发表时间：
2017-09-11
影响因子：
4.6
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Dobrynin G;McAllister TE;Leszczynska KB;Ramachandran S;Krieg AJ;Kawamura A;Hammond EM
大多数实体肿瘤都存在缺氧区(低氧)，而这些区域的细胞侵袭性最强，对治疗也最具抵抗力。低氧诱导因子(HIF)介导的基因表达的广泛变化是导致侵袭性低氧肿瘤表型的重要原因。除了HIF外，多种组蛋白去甲基酶的表达和活性也发生了变化，为延长低氧信号反应提供了第二个机制。在这项研究中，我们证明了HIF-1α的水平直接受抑制性染色质标记H3K9me3的控制。在组蛋白去甲基酶KDM4A耗尽或失活的条件下，H3K9me3聚集在HIF-1α基因座，导致HIF-1α基因表达减少，HIF-1α稳定性降低。在低氧条件下KDM4A的缺失导致HIF-1α介导的转录反应降低，并与与肿瘤侵袭性相关的特征的减少有关，包括侵袭、迁移和氧气消耗。在轻度缺氧条件下，KDM4A对HIF-1α的调节作用最强。这表明KDM4A可以通过增加总可用蛋白来抵消任何剩余的Pro羟基酶活性来增强HIF-1α的功能。
Regions of hypoxia (low oxygen) occur in most solid tumours and cells in these areas are the most aggressive and therapy resistant. In response to decreased oxygen, extensive changes in gene expression mediated by Hypoxia-Inducible Factors (HIFs) contribute significantly to the aggressive hypoxic tumour phenotype. In addition to HIFs, multiple histone demethylases are altered in their expression and activity, providing a secondary mechanism to extend the hypoxic signalling response. In this study, we demonstrate that the levels of HIF-1α are directly controlled by the repressive chromatin mark, H3K9me3. In conditions where the histone demethylase KDM4A is depleted or inactive, H3K9me3 accumulates at the HIF-1α locus, leading to a decrease in HIF-1α mRNA and a reduction in HIF-1α stabilisation. Loss of KDM4A in hypoxic conditions leads to a decreased HIF-1α mediated transcriptional response and correlates with a reduction in the characteristics associated with tumour aggressiveness, including invasion, migration, and oxygen consumption. The contribution of KDM4A to the regulation of HIF-1α is most robust in conditions of mild hypoxia. This suggests that KDM4A can enhance the function of HIF-1α by increasing the total available protein to counteract any residual activity of prolyl hydroxylases.
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影响因子：
8.4
作者：
Hopkinson RJ;Tumber A;Yapp C;Chowdhury R;Aik W;Che KH;Li XS;Kristensen JBL;King ONF;Chan MC;Yeoh KK;Choi H;Walport LJ;Thinnes CC;Bush JT;Lejeune C;Rydzik AM;Rose NR;Bagg EA;McDonough MA;Krojer T;Yue WW;Ng SS;Olsen L;Brennan PE;Oppermann U;Muller-Knapp S;Klose RJ;Ratcliffe PJ;Schofield CJ;Kawamura A
通讯作者：
Kawamura A
影响因子：
56.9
作者：
Jaakkola, P;Mole, DR;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ
影响因子：
16
作者：
Olcina, Monica M.;Foskolou, Iosifina P.;Anbalagan, Selvakumar;Senra, Joana M.;Pires, Isabel M.;Jiang, Yanyan;Ryan, Anderson J.;Hammond, Ester M.
通讯作者：
Hammond, Ester M.
影响因子：
16.6
作者：
Kawamura A;Münzel M;Kojima T;Yapp C;Bhushan B;Goto Y;Tumber A;Katoh T;King ON;Passioura T;Walport LJ;Hatch SB;Madden S;Müller S;Brennan PE;Chowdhury R;Hopkinson RJ;Suga H;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
16.8
作者：
Couture, Jean-Francois;Collazo, Evys;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.