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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