Identification of Mixed Lineage Leukemia 1(MLL1) as a Coactivator of Heat Shock Factor 1(HSF1) in response to Heat Shock Protein 90 (HSP90) Inhibition [Molecular Bases of Disease]

May 15th, 2014 by Chen, Y., Chen, J., Yu, J., Yang, G., Temple, E., Harbinski, F., Gao, H., Wilson, C., Pagliarini, R., Zhou, W.

HSP90 inhibition inhibits cancer cell proliferation through depleting client onco-proteins and shutting down multiple oncogenic pathways, and is therefore an attractive strategy for targeting human cancers. Several HSP90 inhibitors including AUY922 and STA9090 show promising effects in clinical trials. However, the efficacy of HSP90 inhibitors may to be limited by HSF1-mediated feedback mechanisms. Here, we identify through an siRNA screen that the H3K4 methyltransferase MLL1 functions as a coactivator of HSF1 in response to HSP90 inhibition. MLL1 is recruited to the promoters of HSF1-target genes and regulates their expression in response to HSP90 inhibition. In addition, a striking combination effect is observed when MLL1 depletion is combined with HSP90 inhibition in various human cancer cell lines and tumor models. Thus, targeting MLL1 may block a HSF1-mediated feedback mechanism induced by HSP90 inhibition and provide a new avenue to enhance HSP90 inhibitor activity in human cancers.
  • Posted in Journal of Biological Chemistry, Publications
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