Targeting EZH2 in the Treatment of Colon and Rectal Cancer
Abstract
Objective: The Wnt pathway is heavily implicated in the pathogenesis of colorectal cancer (CRC). EZH2-mediated histone methylation has become an attractive area of study in a several cancers. We sought to determine EZH2’s... [ view full abstract ]
Objective: The Wnt pathway is heavily implicated in the pathogenesis of colorectal cancer (CRC). EZH2-mediated histone methylation has become an attractive area of study in a several cancers. We sought to determine EZH2’s role in the development of and potential treatment for CRC as well as any role EZH2 may be playing in the Wnt pathway.
Methods: CRC specimens were interrogated for EZH2 expression in comparison to normal colon mucosa. CRC cells were treated with GSK126, an EZH2 inhibitor, and assessed for cell viability and genetic expression profiles.
Results: EZH2 expression increased as colon tissue progressed from benign epithelium to primary CRC (median 8.03 vs. 20.21 transcripts/million, P<0.0001). GSK126 inhibited cell viability of a variety of CRC cell lines but was more potent in cancer initiating cells than adherent cells in vitro (SW480: IC50 0.300 vs 0.087 µM). Nanostring analysis of treated CRC cells demonstrated a 269-fold increase in the expression of DKK1—a known Wnt inhibitor. This finding was confirmed with a dose-dependent increase in DKK1 protein content by Western blotting. Wnt signaling, measured by LEF1 expression, was decreased by 2.5-fold after GSK126 treatment. The expression of TCF3, a gene whose expression is normally inhibited by Wnt pathway activity, increased by 2.9-fold.
Conclusions: EZH2 is up-regulated in CRC pathogenesis. Pharmacological EZH2 manipulation inhibits CRC cell growth in vitro. The mechanism is at least in part through the inhibition of Wnt pathway signaling. Targeting EZH2 could be a potential treatment approach for CRC.
Authors
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Sushanth Reddy
(University of Alabama - Birmingham)
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Patsy Oliver
(University of Alabama at Birmingham)
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Donald Buchsbaum
(University of Alabama at Birmingham)
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Sooryanarayana Varambally
(University of Alabama at Birmingham)
Topic Area
Surgical Oncology
Session
QS-SurgOnc » Quick-Shot Presentations: Surgical Oncology (15:00 - Thursday, 21st September, Lee 404)