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Colorectal cancer is associated with aberrant activation of the Wnt pathway. β-Catenin plays essential roles in the Wnt pathway by interacting with T-cell factor 4 (TCF4) to transcribe oncogenes. We synthesized a small molecule, referred to as HI-B1, and evaluated signaling changes and biological consequences induced by the compound. HI-B1 inhibited β-catenin/TCF4 luciferase activity and preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. The formation of the β-catenin/TCF4 complex was disrupted by HI-B1 due to the direct interaction of HI-B1 with β-catenin. Colon cancer patient-derived xenograft (PDX) studies showed that a tumor with higher levels of β-catenin expression was more sensitive to HI-B1 treatment, compared to a tumor with lower expression levels of β-catenin. The different sensitivities of PDX tumors to HI-B1 were dependent on the β-catenin expression level and potentially could be further exploited for biomarker development and therapeutic applications against colon cancer., Graphical Abstract Image 1, Highlights • HI-B1 is a synthesized compound identified as a β-catenin inhibitor suppressing the β-catenin-TCF4 protein interaction. • HI-B1 preferentially causes apoptosis in β-catenin-dependent cancer cells. • A colon cancer PDX mouse model with a high level of β-catenin is sensitive to HI-B1. β-catenin is an important protein that facilitates colon cancer. Shin et al. synthesized and identified HI-B1 as a direct β-catenin inhibitor. HI-B1 disrupted formation of the β-catenin-TCF4 protein complex. HI-B1 preferentially caused apoptosis of cancer cells in which the survival is dependent on β-catenin. In a comparison of two colon cancer PDX models with different β-catenin levels, they showed that β-catenin-high PDX is more sensitive to HI-B1 treatment than β-catenin-low PDX. HI-B1 could thus be further developed as a colon cancer drug, and β-catenin expression levels might be a predictive biomarker for colon cancer therapy using β-catenin inhibitors.

Aberrant gene silencing is highly associated with altered cell cycle regulation during carcinogenesis. In particular, silencing of the CDKN2A tumor suppressor gene, which encodes the p16INK4a protein, has a causal link with several different types of cancers. The p16INK4a protein plays an executional role in cell cycle and senescence through the regulation of the cyclin-dependent kinase (CDK) 4/6 and cyclin D complexes. Several genetic and epigenetic aberrations of CDKN2A lead to enhanced tumorigenesis and metastasis with recurrence of cancer and poor prognosis. In these cases, the restoration of genetic and epigenetic reactivation of CDKN2A is a practical approach for the prevention and therapy of cancer. This review highlights the genetic status of CDKN2A as a prognostic and predictive biomarker in various cancers., Highlights • The status of CDKN2A provides epigenetic/genetic information for the cancer patient. • The correlation of p16INK4a and related biomarkers should be considered for prognosis of cancers. • Epigenetic/genetic modulation of changes in CDKN2A might be a promising cancer preventive/therapeutic strategy.