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

作者：Tagde Ashujit; Rajabi Hasan; Stroopinsky Dina; Gali Reddy; Alam Maroof; Bouillez Audrey; Kharbanda Surender; Stone Richard; Avigan David^*; Kufe Donald^*

来源：Oncotarget, 2016, 7(26): 38974-38987.

DOI：10.18632/oncotarget.9777

• MUC1-C
• DNMT1
• DNA methylation
• decitabine
• CDH1

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-kappa B p65 pathway, promotes occupancy of the MUC1-C/NF-kappa B 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.

• 出版日期2016-6-28