Identification of the MLL2 complex as a coactivator for estrogen receptor α

A novel estrogen receptor (ER)alpha coactivator complex, the MLL2 complex, which consists of MLL2, ASH2, RBQ3, and WDR5, was identified. ER alpha directly binds to the MLL2 complex through two LXXLL motifs in a region of MLL2 near the C terminus in a ligand-dependent manner. Disrupting the interaction between ER alpha and the MLL2 complex with small interfering RNAs specific against MLL2 or an MLL2 fragment representing the interacting region with ER alpha significantly inhibited the ER alpha transcription activity. The MLL2 complex was recruited on promoters of ER alpha target genes along with ER alpha upon estrogen stimulation. Inhibition of MLL2 expression decreased the estrogen-induced expression of ER alpha target genes cathepsin D and to a lesser extent pS2. In addition, MCF-7 cell growth was also inhibited by the depletion of MLL2. These results demonstrate that the ER alpha signaling pathway is critically dependent on its direct interaction with the MLL2 complex and suggest a central role for the MLL2 complex in the growth of ER alpha-positive cancer cells.