Aberrant hyperactivation of Wnt signaling, driven by nuclear β-catenin in the colonic
epithelium, represents the seminal event in the initiation and progression of colorectal
cancer (CRC). Despite its established role in CRC tumorigenesis, clinical translation
of Wnt inhibitors remains unsuccessful. Late SV40 factor (LSF; encoded by TFCP2) is a transcription factor and a potent oncogene. We identified a chemotype, named
factor quinolinone inhibitors (FQIs), that specifically inhibits LSF DNA-binding,
partner protein-binding, and transactivation activities. We examined the role of LSF
and FQIs in CRC tumor growth. Herein, we show that LSF and β-catenin interacted in
several CRC cell lines irrespective of their mutational profile, which was disrupted
by FQI2-34. FQI2-34 suppressed Wnt activity in CRC cells in a dose-dependent manner.
Leveraging both allogeneic and syngeneic xenograft models, we show that FQI2-34 suppressed
CRC tumor growth, significantly reduced nuclear β-catenin, and down-regulated Wnt
targets, such as AXIN-2 and SRY-box transcription factor 9, in the xenograft cells.
FQI2-34 suppressed the proliferation of xenograft cells. Adenocarcinomas from a series
of stage IV CRC patients revealed a positive correlation between LSF expression and
Wnt targets (AXIN-2 and SRY-box transcription factor 9) within the CRC cells. Collectively,
this study uncovers the Wnt inhibitory and CRC growth-suppressive effects of these
LSF inhibitors in CRC cells, revealing a novel target in CRC therapeutics.
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Article Info
Publication History
Published online: June 13, 2022
Accepted:
April 11,
2022
Publication stage
In Press Journal Pre-ProofFootnotes
Supported in part by NIH R01HL132325 and R21 DK119740 ; American Heart Association CAT-HD Center grant 857078 (V.C.C. and S.L.); an Ignition Award from the Office of Technology at Boston University (S.E.S., V.C.C., and U.H.); and Shepherd Therapeutics .
S.L. and D.L. share equal authorship.
Disclosures: S.E.S. and U.H. are cofounders of Lamerigen, Inc. S.E.S., E.A.Y., and U.H. received financial support from Shepherd Therapeutics. The remaining authors have no conflicts of interest.
Identification
Copyright
© 2022 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
