Cytoplasmic translocation of MTA1 coregulator promotes de-repression of SGK1 transcription in hypoxic cancer cells
Cytoplasmic translocation of MTA1 coregulator promotes de-repression of SGK1 transcription in hypoxic cancer cells
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DOI：
10.1038/onc.2017.19
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发表时间：
2017-09-14
期刊：
影响因子：
8
通讯作者：
Pillai, M. R.
中科院分区：
文献类型：
--
作者：
Marzook, H.;Deivendran, S.;Pillai, M. R.
染色质重塑因子转移瘤蛋白1（Chromatin remodeling factor metastatic tumor protein 1，MTA 1）是人类肿瘤中表达最高的癌基因之一，在基因表达、细胞存活和促进缺氧反应中起重要作用。成功的癌症进展取决于细胞利用其生存途径适应缺氧微环境的能力。虽然MTA 1是一个应激反应基因，但低氧是否调节其功能及其在参与其他核心应激反应生存途径中的作用仍不清楚。在这里，我们发现，MTA 1是一种新的血清和糖皮质激素诱导激酶1（SGK 1）的辅阻遏物。令人惊讶的是，MTA 1的这种调节辅抑制功能在缺氧下丧失，允许SGK 1表达上调并参与MTA 1-SGK 1轴以利于细胞存活。缺氧显著刺激SGK 1表达的潜在机制包括由于缺氧触发的MTA 1的核质易位而导致SGK 1转录的去抑制。此外，新发现的MTA 1胞质转位依赖于热休克蛋白90（HSP 90）的陪伴功能，并伴随着MTA 1、HSP 90和HIF 1 α复合物的形成，而在常氧条件下则不存在。缺氧引发的MTA 1，SGK 1上调和细胞存活功能的再分布受到药理学SGK 1抑制剂的损害。总之，我们首次报道了MTA 1对SGK 1表达的调节、低氧依赖性MTA 1向细胞质的转运以及SGK 1转录的去抑制。这些发现说明了癌细胞如何利用染色质重塑因子参与核心生存途径以支持其癌性表型，并通过癌症进展中的生理信号揭示了MTA 1-SGK 1轴的新方面。
Chromatin remodeling factor metastatic tumor protein 1 (MTA1), one of the most upregulated oncogene in human cancer, has an important role in gene expression, cell survival and promoting hypoxic response. Successful cancer progression is dependent on the ability of cells to utilize its survival pathways for adapting to hypoxic microenvironment. Although MTA1 is a stress-responsive gene, but whether hypoxia modulates its function and its role in engaging other core stress-responsive survival pathway(s) remains unknown. Here we have discovered that MTA1 is a novel corepressor of serum and glucocorticoid-inducible kinase 1 (SGK1). Surprisingly, this regulatory corepressive function of MTA1 is lost under hypoxia, allowing upregulation of SGK1 expression and engaging the MTA1-SGK1 axis for the benefit of the cell survival. The underlying mechanism of the noticed stimulation of SGK1 expression by hypoxia includes de-repression of SGK1 transcription because of hypoxia-triggered nucleus-to-cytoplasmic translocation of MTA1. In addition, the newly recognized cytoplasmic translocation of MTA1 was dependent on the chaperoning function of heat shock protein 90 (HSP90) and co-accompanied by the formation of MTA1, HSP90 and HIF1 alpha complex under hypoxic condition but not under normoxic condition. Hypoxia-triggered redistribution of MTA1, SGK1 upregulation and cell survival functions were compromised by a pharmacological SGK1 inhibitor. In summary, for the first time, we report MTA1 regulation of SGK1 expression, hypoxia-dependent MTA1 translocation to the cytoplasm and de-repression of SGK1 transcription. These findings illustrate how cancer cells utilize a chromatin remodeling factor to engage a core survival pathway to support its cancerous phenotypes, and reveal new facets of MTA1-SGK1 axis by a physiologic signal in cancer progression.