Tagde, AshujitRajabi, HasanStroopinsky, DinaGali, RayappaAlam, MaroofBouillez, AudreyKharbanda, SurenderStone, RichardAvigan, DavidKufe, Donald2017-01-032016Tagde, Ashujit, Hasan Rajabi, Dina Stroopinsky, Reddy Gali, Maroof Alam, Audrey Bouillez, Surender Kharbanda, Richard Stone, David Avigan, and Donald Kufe. 2016. “MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia.” Oncotarget 7 (26): 38974-38987. doi:10.18632/oncotarget.9777. http://dx.doi.org/10.18632/oncotarget.9777.1949-2553http://nrs.harvard.edu/urn-3:HUL.InstRepos:29739046Aberrant 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.en-USMUC1-CDNMT1DNA methylationdecitabineCDH1Journal Article2017-01-0310.18632/oncotarget.9777