MUC1-C induces DNA methyltransferase 1 and represses tumor suppressor genes in acute myeloid leukemia.
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.
['Tagde|Ashujit|A|', 'Rajabi|Hasan|H|', 'Stroopinsky|Dina|D|', 'Gali|Reddy|R|', 'Alam|Maroof|M|', 'Bouillez|Audrey|A|', 'Kharbanda|Surender|S|', 'Stone|Richard|R|', 'Avigan|David|D|', 'Kufe|Donald|D|']
D051997:ADP-ribosyl Cyclase 1 D015703:Antigens, CD D018952:Antigens, CD34 D001374:Azacitidine D015820:Cadherins D045744:Cell Line, Tumor D002470:Cell Survival D019295:Computational Biology D000076123:DNA (Cytosine-5-)-Methyltransferase 1 D019175:DNA Methylation D000077209:Decitabine D004357:Drug Synergism D015973:Gene Expression Regulation, Leukemic D020868:Gene Silencing D016147:Genes, Tumor Suppressor D006801:Humans D015470:Leukemia, Myeloid, Acute D018396:Mucin-1 D052002:NF-kappa B p50 Subunit D011401:Promoter Regions, Genetic D034741:RNA, Small Interfering D051996:Transcription Factor RelA
MUC1-C DNA methylation DNMT1 CDH1 decitabine