ADNP Is a Therapeutically Inducible Repressor of WNT Signaling in Colorectal Cancer.

Abstract

<b>Purpose:</b> Constitutively active WNT signaling is a hallmark of colorectal cancers and a 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.<b>Experimental Design:</b> We used transcriptomic, proteomic, and <i>in situ</i> 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 <i>in vivo</i> Clinical associations were determined in a cohort of 221 human colorectal cancer cases.<b>Results:</b> 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 <i>in vivo</i> Treatment with subnarcotic doses of ketamine induced ADNP expression, significantly inhibited tumor growth, and prolonged survival of tumor-bearing animals. In human patients with colon cancer, high ADNP expression was linked to good prognosis.<b>Conclusions:</b> Our findings indicate that ADNP is a tumor suppressor and promising prognostic marker, and that ketamine treatment with ADNP induction is a potential therapeutic approach that may add benefit to current treatment protocols for patients with colorectal cancer. <i>Clin Cancer Res; 23(11); 2769-80. ©2016 AACR</i>.