Work

MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia

Year: 2016

Type: article

Abstract: // Ashujit Tagde 1 , Hasan Rajabi 1 , Dina Stroopinsky 2 , Reddy Gali 3 , Maroof Alam 1 , Audrey Bouillez 1 , Surender Kharbanda 1 , Richard Stone 1 , David Avigan 2 and Donald Kufe 1 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 Correspondence to: 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 Abstract 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.9777