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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents
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MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents

机译：MAGE-A肿瘤抗原通过组蛋白脱乙酰基酶募集靶向p53反式激活功能，并赋予对化学治疗剂的抗性

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摘要

The MAGE gene family is characterized by a conserved domain (MAGE Homology Domain). A subset of highly homologous MAGE genes (group A; IMAGE-A) belong to the chromosome X-clustered cancer/testis antigens. MAGE-A genes are normally expressed in the human germ line and overexpressed in various tumor types; however, their biological function is largely unknown. Here we present evidence indicating that MageA2 protein, belonging to the MAGE-A subfamily, confers wild-type-p53-sensitive resistance to etoposide (ET) by inducing a novel p53 inhibitory loop involving recruitment of histone deacetylase 3 (HDAC3) to MageA2/p53 complex, thus strongly down-regulating p53 transactivation function. In fact, enhanced MageA2 protein levels, in addition to ET resistance, correlate with impaired acetylation of both p53 and histones surrounding p53-binding sites. Association between MAGE-A expression levels and resistance to ET treatment is clearly shown in short-term cell lines obtained from melanoma biopsies harboring wild-type-p53, whereas cells naturally, or siRNA-mediated expressing low IMAGE-A levels, correlate with enhanced p53-dependent sensitivity to ET. In addition, combined trichostatin A/ET treatment in melanoma cells expressing high MAGE-A levels reestablishes p53 response and reverts the chemoresistance.
机译：MAGE基因家族的特征在于保守结构域（MAGE Homology Domain）。高度同源的MAGE基因的一个子集（A组； IMAGE-A）属于X染色体集群的癌症/睾丸抗原。 MAGE-A基因通常在人类种系中表达，并在各种肿瘤类型中过表达；然而，它们的生物学功能很大程度上未知。在这里，我们提供的证据表明，属于MAGE-A亚科的MageA2蛋白通过诱导涉及组蛋白脱乙酰基酶3（HDAC3）募集的新型p53抑制环，赋予了对依托泊苷（ET）的野生型p53敏感性耐药。 p53复合物，因此强烈下调了p53反式激活功能。实际上，除ET耐药性外，增强的MageA2蛋白水平还与p53和p53结合位点周围的组蛋白的乙酰化受损有关。从具有野生型p53的黑色素瘤活检组织获得的短期细胞系中清楚地显示了MAGE-A表达水平与对ET治疗的抗性之间的关联，而天然细胞或siRNA介导的表达低IMAGE-A水平的细胞与增强MAGE-A表达有关p53对ET的敏感性。此外，在表达高MAGE-A水平的黑素瘤细胞中联合曲古抑素A / ET处理可重新建立p53反应并恢复化学耐药性。

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