Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem-like Cell Traits in Breast Cancer
Epigenetic Activation of TWIST1 by MTDH Promotes Cancer Stem-like Cell Traits in Breast Cancer
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MTDH 对 TWIST1 的表观遗传激活促进乳腺癌中的癌症干细胞样细胞特征
DOI：
10.1158/0008-5472.can-15-0930
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Hu, Guohong
中科院分区：
文献类型：
--
作者：
Liang, Yajun;Hu, Jing;Hu, Guohong
癌症干细胞样细胞（CSC）是一种细胞亚群，可以重新启动肿瘤，抵抗化疗，并引起转移。Metadherin（MTDH）广泛参与肿瘤生长、耐药性、复发和转移，但其分子作用机制尚不清楚。在这里，我们报告说，MTDH驱动CSC的扩张，通过促进TWIST 1的表达，一个转录因子的癌细胞的干细胞和转移的关键。MTDH通过促进TWIST 1启动子上的组蛋白H3乙酰化间接激活TWIST 1表达，该过程由组蛋白乙酰转移酶CBP介导。机制研究表明，MTDH与CBP相互作用，并阻止其泛素介导的降解，许可其转录激活TWIST 1。在乳腺癌的临床标本中，MTDH表达与TWIST 1表达和CSC丰度呈正相关。总体而言，我们的工作揭示了MTDH通过调节TWIST 1促进CSC积累和乳腺致瘤性，加深了对MTDH在癌症中功能的理解。（C）2015年AACR。
Cancer stem-like cells (CSC) are a cell subpopulation that can reinitiate tumors, resist chemotherapy, and give rise to metastases. Metadherin (MTDH) contributes widely to tumor growth, drug resistance, relapse, and metastasis, but its molecular mechanisms of action are not well understood. Here, we report that MTDH drives CSC expansion by promoting the expression of TWIST1, a transcription factor critical for cancer cell stemness and metastasis. MTDH activates TWIST1 expression indirectly by facilitating histone H3 acetylation on the TWIST1 promoter, a process mediated by the histone acetyltransferase CBP. Mechanistic investigations showed that MTDH interacts with CBP and prevents its ubiquitin-mediated degradation, licensing its transcriptional activation of TWIST1. In clinical specimens of breast cancer, MTDH expression correlates positively with TWIST1 expression and CSC abundance. Overall, our work revealed that MTDH promotes CSC accumulation and breast tumorigenicity by regulating TWIST1, deepening the understanding of MTDH function in cancer. (C)2015 AACR.