Purpose: Constitutively active WNT signaling is hallmark of colorectal cancers and driver of malignant tumor progression. Therapeutic targeting of WNT signaling is difficult due to high pathway complexity and its role in tissue homeostasis. Here we identify the transcription factor ADNP as a pharmacologically inducible repressor of WNT signaling in colon cancer. Experimental design: We used transcriptomic, proteomic, and in situ analyses to identify ADNP expression in colorectal cancer, and cell biology approaches to determine its function. We induced ADNP expression in colon cancer xenografts by low-dose ketamine in vivo. Clinical associations were determined in a cohort of 221 human colorectal cancer cases. Results: ADNP was overexpressed in colon cancer cells with high WNT activity, where it acted as a WNT repressor. Silencing ADNP expression increased migration, invasion and proliferation of colon cancer cells, and accelerated tumor growth in xenografts in vivo. Treatment with sub-narcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor bearing animals. In human colon cancer patients, high ADNP expression was linked to good prognosis. Conclusion: Our findings indicate ADNP as a tumor suppressor and promising prognostic marker, and ketamine treatment with ADNP induction as a potential therapeutic approach that may add to current treatment protocols with benefits for colorectal cancer patients.
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