TCF‐1 Regulation By A Wnt‐Kinase Network In Colon Cancer

Abstract

TCF‐1 and TCF‐4 are the major transducers of Wnt signaling in the intestine and the oncogenic drivers of colon cancer. However, knock‐out of the TCF1 gene leads to intestinal tumors while knockout of TCF‐4 suppresses growth and maintenance of crypt stem cells. These phenotypes suggest that TCF‐4 is Wnt‐promoting and TCF‐1 is a tumor suppressor. We show that a truncated dominant negative isoform of TCF‐1 (dnTCF‐1) predominates in the normal colon and is equally distributed between nuclear and cytoplasmic compartments in normal crypts. However, in primary human colon tumors, TCF‐1 is often cytoplasmic while TCF‐4 remains nuclear. This shift to the cytoplasm is regulated by a CaMKII/TAK1/NLK kinase cascade that triggers secretion of a Wnt ligand to selectively export TCF‐1 from the nucleus. In colon cancer, TCF‐1 expression is altered so that dnTCF‐1 is downregulated while to full‐length, Wnt‐promoting isoforms are upregulated. Our study shows that control of nuclear export is an important mechanism for regulating the balance of TCFs and that a Wnt/CaMKII kinase signal plays a key role in modulating Wnt activity in the human colon.Supported by NIH