Nuclear IKK activity leads to dysregulated notch-dependent gene expression in colorectal cancer.
Nuclear functions for IkappaB 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, IKKalpha 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 IKKalpha 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.
Fernández-Majada
V
V
Centre Oncologia Molecular, Institut d'Investigació Biomèdica de Bellvitge, Gran Via Km 2.7, Hospitalet, 08907 Barcelona, Spain.
Aguilera
C
C
Villanueva
A
A
Vilardell
F
F
Robert-Moreno
A
A
Aytés
A
A
Real
F X
FX
Capella
G
G
Mayo
M W
MW
Espinosa
L
L
Bigas
A
A
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000201:enzymology*; D015179:Colorectal Neoplasms / Q000235:genetics*; D004789:Enzyme Activation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051550:I-kappa B Kinase / Q000502:physiology*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000502:physiology; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D051880:Receptors, Notch / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D016328:NF-kappa B; D009570:Nitriles; D051880:Receptors, Notch; D012097:Repressor Proteins; D013450:Sulfones; D051550:I-kappa B Kinase