1. Department of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, South Korea
2. Howard Hughes Medical Institute, University of California, San Diego, Department and School of Medicine, La Jolla, California 92093-0648, USA
3. Howard Hughes Medical Institute, Department of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA
4. Institute of Clinical Chemistry and Pathobiochemistry, Charite - Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany
5. Department of Medicine, Division of Endocrinology and Metabolism, School of Medicine, University of California, San Diego, San Diego, California 92093, USA
6. These authors contributed equally to this work

Correspondence to: Michael G. Rosenfeld²Sung Hee Baek¹ Correspondence and requests for materials should be addressed to S.H.B. (Email: sbaek@snu.ac.kr) or M.G.R. (Email: mrosenfeld@ucsd.edu).

Abstract

Defining the molecular strategies that integrate diverse signalling pathways in the expression of specific gene programmes that are critical in homeostasis and disease remains a central issue in biology. This is particularly pertinent in cancer biology because downregulation of tumour metastasis suppressor genes is a common occurrence^{1, 2}, and the underlying molecular mechanisms are not well established. Here we report that the downregulation of a metastasis suppressor gene, KAI1, in prostate cancer cells involves the inhibitory actions of -catenin, along with a reptin chromatin remodelling complex. This inhibitory function of -catenin–reptin requires both increased -catenin expression and recruitment of histone deacetylase activity. The coordinated actions of -catenin–reptin components that mediate the repressive state serve to antagonize a Tip60 coactivator complex^{3, 4, 5, 6, 7, 8} that is required for activation; the balance of these opposing complexes controls the expression of KAI1 and metastatic potential. The molecular mechanisms underlying the antagonistic regulation of -catenin–reptin and the Tip60 coactivator complexes for the metastasis suppressor gene, KAI1, are likely to be prototypic of a selective downregulation strategy for many genes, including a subset of NF-B target genes.

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