Hypoxia is a major driving force of cancer invasion and metastasis. Here we show that death domain-associated protein (Daxx) acts to negatively regulate hypoxia-induced cell dissemination and invasion by inhibiting the HIF-1α/HDAC1/Slug pathway. Daxx directly binds to the DNA-binding domain of Slug, impeding histone deacetylase 1 (HDAC1) recruitment and antagonizing Slug E-box binding. This, in turn, stimulates E-cadherin and occludin expression and suppresses Slug-mediated epithelial-mesenchymal transition (EMT) and cell invasiveness. Under hypoxic conditions, stabilized hypoxia-inducible factor (HIF)-1α downregulates Daxx expression and promotes cancer invasion, whereas re-expression of Daxx represses hypoxia-induced cancer invasion. Daxx also suppresses Slug-mediated lung cancer metastasis in an orthotopic lung metastasis mouse model. Using clinical tumour samples, we confirmed that the HIF-1α/Daxx/Slug pathway is an outcome predictor. Our results support that Daxx can act as a repressor in controlling HIF-1α/HDAC1/Slug-mediated cancer cell invasion and is a potential therapeutic target for inhibition of cancer metastasis.

译文

:缺氧是癌症侵袭和转移的主要驱动力。在这里,我们显示死亡域相关蛋白(Daxx)通过抑制HIF-1α/ HDAC1 / Slug途径负调控缺氧诱导的细胞扩散和侵袭。 Daxx直接与Slug的DNA结合域结合,阻止组蛋白脱乙酰基酶1(HDAC1)募集并拮抗Slug E-box的结合。反过来,这会刺激E-cadherin和occludin的表达,并抑制Slug介导的上皮-间质转化(EMT)和细胞侵袭性。在缺氧条件下,稳定的缺氧诱导因子(HIF)-1α下调Daxx表达并促进癌症侵袭,而Daxx的重新表达则抑制缺氧诱导的癌症侵​​袭。 Daxx还可以在原位肺转移小鼠模型中抑制Slug介导的肺癌转移。使用临床肿瘤样本,我们证实了HIF-1α/ Daxx / Slug途径是结果的预测指标。我们的结果支持Daxx可以作为控制HIF-1α/ HDAC1 / Slug介导的癌细胞侵袭的阻遏物,并且是抑制癌症转移的潜在治疗靶标。

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