Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

doi:10.1073/pnas.0606476104

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

*Centre Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge, Gran Via Km 2.7, Hospitalet, 08907 Barcelona, Spain;
^†Laboratori de Recerca Translacional, Institut d'Investigació Biomèdica de Bellvitge-Institut Català de Oncologia, Gran Via Km 2.7, Hospitalet, 08907 Barcelona, Spain;
^‡Unitat de Biologia Celular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, 08003 Barcelona, Spain; and
^§Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908

Edited by Mark T. Groudine, Fred Hutchinson Cancer Research Center, Seattle, WA, and approved November 2, 2006 (received for review July 28, 2006)

Abstract

Nuclear functions for IκB kinase (IKK), including phosphorylation of histone H3 and nuclear corepressors, have been recently described. Here, we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor that is aberrantly localized in the cytoplasm. In these tumors, IKKα associates to the chromatin of specific Notch targets, leading to the release of SMRT. Abrogation of IKK activity by BAY11-7082 or by expressing dominant negative IKKα restores the association of SMRT with Notch target genes, resulting in specific gene repression. Finally, BAY11-7082 significantly reduces tumor size in colorectal cancer xenografts (CRC-Xs) implanted in nude mice.

Footnotes

^¶To whom correspondence may be addressed. E-mail: llespinosa{at}idibell.org or abigas{at}idibell.org
Author contributions: L.E. and A.B. contributed equally to this work; G.C., L.E., and A.B. designed research; V.F.-M., C.A., A.V., A.R.-M., A.A., and L.E. performed research; M.W.M. contributed new reagents/analytic tools; V.F.-M., F.V., F.X.R., G.C., L.E., and A.B. analyzed data; and L.E. and A.B. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0606476104/DC1.
Abbreviations:

IKK,

IκB kinase;

IHC,

immunohistochemistry;

CRC-X,

colorectal cancer xenograft.