Cancer esearch apeutics , Targets , and Chemical Biology one Methyltransferase MLL 1 Regulates MDR 1 R nscription and Chemoresistance

nloaded multidrug resistance 1 gene (MDR1) encodes P-glycoprotein (Pgp), a member of the ATP-binding te (ABC) transporter family that confers tumor drug resistance by actively effluxing a number of mor agents. We had previously shown that MDR1 transcription is regulated by epigenetic events such tone acetylation, and had identified the histone acetylase P/CAF and the transcription factor NF-Y as ctors mediating the enzymatic and DNA-anchoring functions, respectively, at the MDR1 promoter. It so been shown that MDR1 activation is accompanied by increased methylation on lysine 4 of histone 3K4). In this study, we further investigated histone methylation in MDR1 regulation and function. We that the mixed lineage leukemia 1 (MLL1) protein, a histone methyltransferase specific for H3K4, is ed for MDR1 promoter methylation, as knockdown of MLL1 resulted in a decrease in MDR1 expreshe regulation of MDR1 by MLL1 has functional consequences in that downregulation of MLL1 led to sed retention of the Pgp-specific substrate DIOC2(3), as well as increased cellular sensitivity to several bstrates. Regulation of MDR1 by MLL1 was dependent on the CCAAT box within the proximal MDR1 ter, similar to what we had shown for MDR1 promoter acetylation, and also requires NF-Y. Finally, pression of the most prevalent MLL fusion protein, MLL-AF4, led to increased MDR1 expression. This first identification of a histone methyltransferase and its leukemogenic rearrangement that regulates is the expression of an ABC drug transporter, suggesting a new target for circumvention of tumor multidrug resistance. Cancer Res; 70(21); 8726–35. ©2010 AACR.