DNA methylation by DNMT1 and DNMT3b methyltransferases is driven by the MUC1-C oncoprotein in human carcinoma cells

被引：77

作者：

Rajabi, H. ^{[1
]}

Tagde, A. ^{[1
]}

Alam, M. ^{[1
]}

Bouillez, A. ^{[1
]}

Pitroda, S. ^{[2
]}

Suzuki, Y. ^{[1
,3
]}

Kufe, D. ^{[1
]}

机构：

[1] Harvard Med Sch, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[2] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA

[3] Osaka Police Hosp, Dept Surg Gastroenterol, Osaka, Osaka 5430035, Japan

来源：

ONCOGENE | 2016年 / 35卷 / 50期

基金：

美国国家卫生研究院;

关键词：

TRANSCRIPTIONAL REGULATION; DE-NOVO; EXPRESSION; 3B; 3A; EPIGENETICS; PROGNOSIS; PATHWAY; TARGET; GENES;

D O I：

10.1038/onc.2016.180

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Aberrant expression of the DNA methyltransferases (DNMTs) and disruption of DNA methylation patterns are associated with carcinogenesis and cancer cell survival. The oncogenic MUC1-C protein is aberrantly overexpressed in diverse carcinomas; however, there is no known link between MUC1-C and DNA methylation. Our results demonstrate that MUC1-C induces the expression of DNMT1 and DNMT3b, but not DNMT3a, in breast and other carcinoma cell types. We show that MUC1-C occupies the DNMT1 and DNMT3b promoters in complexes with NF-kappa B p65 and drives DNMT1 and DNMT3b transcription. In this way, MUC1-C controls global DNA methylation as determined by analysis of LINE-1 repeat elements. The results further demonstrate that targeting MUC1-C downregulates DNA methylation of the CDH1 tumor suppressor gene in association with induction of E-cadherin expression. These findings provide compelling evidence that MUC1-C is of functional importance to induction of DNMT1 and DNMT3b and, in turn, changes in DNA methylation patterns in cancer cells.

引用

页码：6439 / 6445

页数：7

共 41 条

[1] MUC1 oncoprotein activates the IκB kinase β complex and constitutive NF-κB signalling [J].