Transcription factor AP-2α regulates acute myeloid leukemia cell proliferation by influencing Hoxa gene expression

Transcription factor AP-2 alpha mediates transcription of a number of genes implicated in mammalian development, cell proliferation and carcinogenesis. In the current study, we identified Hoxa7, Hoxa9 and Hox cofactor Meis1 as AP-2 alpha target genes, which are involved in myeloid leukemogenesis. Luciferase reporter assays revealed that overexpression of AP-2 alpha activated transcription activities of Hoxa7, Hoxa9 and Meisl, whereas siRNA of AP-2 alpha inhibited their transcription activities. We found that AP-2 binding sites in regulatory regions of three genes activated their transcription by mutant analysis and AP-2 alpha could interact with AP-2 binding sites in vivo by chromatin immunoprecipitation (ChIP). Further results showed that the AP-2 alpha shRNA efficiently inhibited mRNA and protein levels of Hoxa7, Hoxa9 and Meis1 in AML cell lines U937 and HL60. Moreover, decreased expression of AP-2 alpha resulted in a significant reduction in the growth and proliferation of AML cells in vitro. Remarkably, AP-2 alpha knockdown leukemia cells exhibit decreased tumorigenicity in vivo compared with controls. Finally, AP-2 alpha and target genes in clinical acute myeloid leukemia samples of M5b subtype revealed variable expression levels and broadly paralleled expression. These data support a role of AP-2 alpha in mediating the expression of Hoxa genes in acute myeloid leukemia to influence the proliferation and cell survival. (C) 2013 Elsevier Ltd. All rights reserved.