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Huo HR , Magro PG , Pietsch EC , Patel BB , Scotto KW
Histone Methyltransferase MLL1 Regulates MDR1 Transcription and Chemoresistance
Cancer Research. 2010 Nov;70(21) :8726-8735
AbstractThe multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding cassette (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of antitumor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such as histone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as the factors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It has also been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone H3 (H3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We show that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is required for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expression. The regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to increased retention of the Pgp-specific substrate DIOC2(3), as well as increased cellular sensitivity to several Pgp substrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 promoter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, overexpression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This is the first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance. Cancer Res; 70(21); 8726-35. (C)2010 AACR.
NotesHuo, Hairong Magro, Pellegrino G. Pietsch, E. Christy Patel, Brijesh B. Scotto, Kathleen W. Laboratory Support Service Shared Resource of The Cancer Institute of New Jersey [P30-CA072720]; NIH NCI Cancer Center [P30-CA072720] Laboratory Support Service Shared Resource of The Cancer Institute of New Jersey (P30-CA072720) and supported by NIH NCI Cancer Center Core Grant P30-CA072720. 50 Amer assoc cancer research; 615 chestnut st, 17th floor, philadelphia, pa 19106-4404 usa 673mj