Priority Research Papers:
MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia
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Ashujit Tagde1, Hasan Rajabi1, Dina Stroopinsky2, Reddy Gali3, Maroof Alam1, Audrey Bouillez1, Surender Kharbanda1, Richard Stone1, David Avigan2 and Donald Kufe1
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
2 Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3 Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA
David Avigan, email:
Donald Kufe, email:
Keywords: MUC1-C, DNMT1, DNA methylation, decitabine, CDH1
Received: April 25, 2016 Accepted: May 22, 2016 Published: June 01, 2016
Aberrant DNA methylation is a hallmark of acute myeloid leukemia (AML); however, the regulation of DNA methyltransferase 1 (DNMT1), which is responsible for maintenance of DNA methylation patterns, has largely remained elusive. MUC1-C is a transmembrane oncoprotein that is aberrantly expressed in AML stem-like cells. The present studies demonstrate that targeting MUC1-C with silencing or a pharmacologic inhibitor GO-203 suppresses DNMT1 expression. In addition, MUC1 expression positively correlates with that of DNMT1 in primary AML cells, particularly the CD34+/CD38- population. The mechanistic basis for this relationship is supported by the demonstration that MUC1-C activates the NF-κB p65 pathway, promotes occupancy of the MUC1-C/NF-κB complex on the DNMT1 promoter and drives DNMT1 transcription. We also show that targeting MUC1-C substantially reduces gene promoter-specific DNA methylation, and derepresses expression of tumor suppressor genes, including CDH1, PTEN and BRCA1. In support of these results, we demonstrate that combining GO-203 with the DNMT1 inhibitor decitabine is highly effective in reducing DNMT1 levels and decreasing AML cell survival. These findings indicate that (i) MUC1-C is an attractive target for the epigentic reprogramming of AML cells, and (ii) targeting MUC1-C in combination with decitabine is a potentially effective clinical approach for the treatment of AML.
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