MUC1-C drives MYC in multiple myeloma.
MUC1-C drives MYC in multiple myeloma.
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DOI：
10.1182/blood-2015-07-659151
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发表时间：
2016-05
期刊：
影响因子：
20.3
通讯作者：
Ashujit Tagde;H. Rajabi;Audrey Bouillez;Maroof Alam;R. Gali;S. Bailey;Y. Tai;T. Hideshima;K. Anderson;D. Avigan;D. Kufe
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文献类型：
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作者：
Ashujit Tagde;H. Rajabi;Audrey Bouillez;Maroof Alam;R. Gali;S. Bailey;Y. Tai;T. Hideshima;K. Anderson;D. Avigan;D. Kufe
多发性骨髓瘤（MM）细胞系和原发肿瘤细胞依赖MYC癌蛋白生存。然而，MYC在MM细胞中的表达上调机制尚不清楚。mucin 1 c末端亚基（MUC1-C）是一种致癌跨膜蛋白，在MM细胞系和原发肿瘤样本中异常表达。目前的研究表明，通过聚集规律间隔短回文重复(CRISPR)/CRISPR相关蛋白9编辑或GO-203抑制剂沉默MUC1-C与MYC信使RNA和蛋白的下调有关。结果表明MUC1-C占据MYC启动子，通过β-catenin/transcription factor 4 （TCF4）介导的机制激活MYC基因。通过这种方式，MUC1-C(1)增加了MYC启动子上β-catenin的占用，(2)与β-catenin和TCF4形成复合物，进而(3)驱动MYC转录。利用实时定量逆转录聚合酶链反应阵列对MM细胞进行分析进一步表明，沉默MUC1- c与MYC靶基因下调有关，包括CCND2、hTERT和GCLC。芯片数据集的分析进一步表明，在800多名MM患者的MM进展和原代细胞中，MUC1水平与MYC表达呈正相关。这些发现共同提供了令人信服的证据，MUC1-C驱动MYC在MM中的表达。
Multiple myeloma (MM) cell lines and primary tumor cells are addicted to the MYC oncoprotein for survival. Little is known, however, about how MYC expression is upregulated in MM cells. The mucin 1 C-terminal subunit (MUC1-C) is an oncogenic transmembrane protein that is aberrantly expressed in MM cell lines and primary tumor samples. The present studies demonstrate that targeting MUC1-C with silencing by clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 editing or with the GO-203 inhibitor is associated with downregulation of MYC messenger RNA and protein. The results show that MUC1-C occupies the MYC promoter and thereby activates the MYC gene by a β-catenin/transcription factor 4 (TCF4)-mediated mechanism. In this way, MUC1-C (1) increases β-catenin occupancy on the MYC promoter, (2) forms a complex with β-catenin and TCF4, and, in turn, (3) drives MYC transcription. Analysis of MM cells using quantitative real-time reverse transcription polymerase chain reaction arrays further demonstrated that silencing MUC1-C is associated with downregulation of MYC target genes, including CCND2, hTERT, and GCLC Analysis of microarray data sets further demonstrated that MUC1 levels positively correlate with MYC expression in MM progression and in primary cells from over 800 MM patients. These findings collectively provide convincing evidence that MUC1-C drives MYC expression in MM.