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A TWIST1-MLL-WDR5-HOTTIP Complex Regulates HOXA9 Chromatin to Facilitate Metastasis of Prostate Cancer Rajendra P. Gajula1, Russell D. Williams1, Reem Malek1, Katriana Nugent1, Amanda J. Walker1, Sivarajan T. Chettiar1, Hailun Wang1, Kekoa Taparra1, Jessica cades1, Joseph M. Herman1 and Phuoc T. Tran1 Hoxa9 is Necessary for Twist1 Phenotypes Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work Summary: Hoxa9 Phenotype Twist-shHoxa9 Hoxa9 Overexpression EMT Markers -- Partial Induction Migration Decreased Increased Invasion Decreased Inceased Anoikis Resistance Decreased Pending Clonogenicity Decreased Increased Soft Agar Decreased No Effect Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work Histone Methyltransferase Complexes • Histone modifications: – H3K27: silencing – H3K4: activation – H3K79: ambiguous, but known to activate Hoxa9 transcription – Bivalence: both activating and silencing modifications present. Nature Reviews Molecular Cell Biology 6, 838-849 (November 2005) Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work HOTTIP: A lincRNA That Regulates the HOXA Cluster • HOTTIP is a lincRNA encoded by a gene in the 5’ region of the HOXA cluster. • HOTTIP activates the HOXA cluster posterior genes via an interaction with an MLL-WDR5 histone methyltransferase complex that increases H3K4me3 activation marks. Wang et. al. Nature 472:120 (2011) Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work Does Involvement of Hoxa9 Suggest a Role for histone methyltransferases? • MLL2 (encoded by KTM2D) mutations common in lethal, castration resistant prostate cancers. • MLL2 is a histone methyltransferase. • In AML, MLL2 mutations are common, and Hoxa9 overexpression is required for survival of MLL2-mutant cells. Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work Proposed Mechanism Introduction: EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work Summary: Hoxa9 Mediates Twist1 Induction of EMT Phenotype • Twist1 expression induces aggressive metastatic phenotype in prostate cancer through EMT. • Structure-function mutants modulate intensity of Twist1-induced phenotype. • Gene expression analysis of structure-function mutants suggested role for Hoxa9. • Hoxa9 is necessary for induction of Twist1-induced EMT phenotype. • Twist1 interacts with HOTTIP and a MLL-WDR5 methyltransferase complex to regulate Hoxa9 chromatin and expression by increasing H3K4me3 chromatin marks. Introduction:EMT and Twist1 Involvement of Hoxa9 Mechanism Conclusions/ Future Work