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.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ashujit
A
Tagde
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Hasan
H
Rajabi
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Dina
D
Stroopinsky
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
Reddy
R
Gali
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Maroof
M
Alam
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Audrey
A
Bouillez
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Surender
S
Kharbanda
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Richard
R
Stone
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
David
D
Avigan
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Donald
D
Kufe
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000378:metabolism; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D019295:Computational Biology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1 / Q000378:metabolism*; 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 / Q000235:genetics / Q000378:metabolism*; D018396:Mucin-1 / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
D015703:Antigens, CD; D018952:Antigens, CD34; C513384:CDH1 protein, human; D015820:Cadherins; C060192:MUC1 protein, human; D018396:Mucin-1; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; C000619380:DNMT1 protein, human; D051997:ADP-ribosyl Cyclase 1; D001374:Azacitidine
CDH1; DNA methylation; DNMT1; MUC1-C; decitabine