Targeted disruption of the BCL9/β-catenin complex inhibits oncogenic Wnt signaling.
Deregulated Wnt/β-catenin signaling underlies the pathogenesis of a broad range of human cancers, yet the development of targeted therapies to disrupt the resulting aberrant transcription has proved difficult because the pathway comprises large protein interaction surfaces and regulates many homeostatic functions. Therefore, we have directed our efforts toward blocking the interaction of β-catenin with B cell lymphoma 9 (BCL9), a co-activator for β-catenin-mediated transcription that is highly expressed in tumors but not in the cells of origin. BCL9 drives β-catenin signaling through direct binding mediated by its α-helical homology domain 2. We developed a stabilized α helix of BCL9 (SAH-BCL9), which we show targets β-catenin, dissociates native β-catenin/BCL9 complexes, selectively suppresses Wnt transcription, and exhibits mechanism-based antitumor effects. SAH-BCL9 also suppresses tumor growth, angiogenesis, invasion, and metastasis in mouse xenograft models of Colo320 colorectal carcinoma and INA-6 multiple myeloma. By inhibiting the BCL9-β-catenin interaction and selectively suppressing oncogenic Wnt transcription, SAH-BCL9 may serve as a prototype therapeutic agent for cancers driven by deregulated Wnt signaling.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Kohichi
K
Takada
Di
D
Zhu
Gregory H
GH
Bird
Kumar
K
Sukhdeo
Jian-Jun
JJ
Zhao
Mala
M
Mani
Madeleine
M
Lemieux
Daniel E
DE
Carrasco
Jeremy
J
Ryan
David
D
Horst
Mariateresa
M
Fulciniti
Nikhil C
NC
Munshi
Wenqing
W
Xu
Andrew L
AL
Kung
Ramesh A
RA
Shivdasani
Loren D
LD
Walensky
Daniel Ruben
DR
Carrasco
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000473:pathology; D018390:Gene Targeting; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D009857:Oncogenes / Q000235:genetics*; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D051820:TCF Transcription Factors / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D060449:Wnt Signaling Pathway / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
C111180:BCL9 protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D051820:TCF Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin