DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression.
DOT1L cooperates with the c-Myc-p300 complex to epigenetically derepress CDH1 transcription factors in breast cancer progression.
复制标题
DOI：
10.1038/ncomms8821
复制
发表时间：
2015-07-22
影响因子：
16.6
通讯作者：
Kong G
中科院分区：
文献类型：
--
作者：
Cho MH;Park JH;Choi HJ;Park MK;Won HY;Park YJ;Lee CH;Oh SH;Song YS;Kim HS;Oh YH;Lee JY;Kong G
DOT 1 L已成为MLL相关白血病的抗癌靶点;然而，其在实体瘤中的功能作用在很大程度上是未知的。在这里，我们确定DOT 1 L与c-Myc和p300乙酰转移酶合作，表观遗传激活乳腺癌进展中的上皮间质转化（EMT）调节因子。DOT 1 L通过与c-Myc-p300复合物相互作用识别SNAIL、ZEB 1和ZEB 2启动子，并促进赖氨酸-79甲基化和乙酰化向组蛋白H3，导致HDAC 1和DNMT 1在该区域解离。DOT 1 L-c-Myc-p300复合物上调这些EMT调节剂增强了EMT诱导的乳腺癌干细胞（CSC）样特性。此外，体内原位异种移植模型表明，DOT 1 L是乳腺上皮细胞恶性转化和乳腺肿瘤发生和转移所必需的。临床上，DOT 1 L表达与乳腺癌的较差生存率和侵袭性相关。综上所述，我们认为DOT 1 L和c-Myc-p300的协同作用是通过促进EMT/CSC获得乳腺癌侵袭性表型的关键。 DOT 1 L是白血病的抗癌治疗靶点，但在实体瘤中的作用知之甚少。在这里，作者表明DOT 1 L表达与生存率低和侵袭性癌症相关，有助于在乳腺癌进展过程中表观遗传激活上皮-间质转化。
DOT1L has emerged as an anticancer target for MLL-associated leukaemias; however, its functional role in solid tumours is largely unknown. Here we identify that DOT1L cooperates with c-Myc and p300 acetyltransferase to epigenetically activate epithelial–mesenchymal transition (EMT) regulators in breast cancer progression. DOT1L recognizes SNAIL, ZEB1 and ZEB2 promoters via interacting with the c-Myc-p300 complex and facilitates lysine-79 methylation and acetylation towards histone H3, leading to the dissociation of HDAC1 and DNMT1 in the regions. The upregulation of these EMT regulators by the DOT1L-c-Myc-p300 complex enhances EMT-induced breast cancer stem cell (CSC)-like properties. Furthermore, in vivo orthotopic xenograft models show that DOT1L is required for malignant transformation of breast epithelial cells and breast tumour initiation and metastasis. Clinically, DOT1L expression is associated with poorer survival and aggressiveness of breast cancers. Collectively, we suggest that cooperative effect of DOT1L and c-Myc-p300 is critical for acquisition of aggressive phenotype of breast cancer by promoting EMT/CSC. DOT1L is an anti-cancer therapeutic target in leukaemia but has a poorly understood role in solid tumours. Here the authors show that DOT1L expression is associated with poor survival and aggressive cancers by helping to epigenetically activate the epithelial-mesenchymal transition during breast cancer progression.