Nuclear IKK Activity Leads to Dysregulated Notch-dependent Gene Expression in Colorectal Cancer

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2006 Dec 28

PMID 17190815

Citations 64

Authors

V Fernandez-Majada

C Aguilera

A Villanueva

F Vilardell

A Robert-Moreno

A Aytes

F X Real

G Capella

M W Mayo

L Espinosa

A Bigas

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Bioinformatic Analysis of Complex Genes Expression in Selected Gastrointestinal Cancers.

Zebrowska-Nawrocka M, Szmajda-Krygier D, Krygier A, Jelen A, Balcerczak E Int J Mol Sci. 2024; 25(18).

PMID: 39337357 PMC: 11432643. DOI: 10.3390/ijms25189868.

Unraveling the Complex Interconnection between Specific Inflammatory Signaling Pathways and Mechanisms Involved in HIV-Associated Colorectal Oncogenesis.

Damane B, Mulaudzi T, Kader S, Naidoo P, Savkovic S, Dlamini Z Cancers (Basel). 2023; 15(3).

PMID: 36765706 PMC: 9913377. DOI: 10.3390/cancers15030748.

The role of Hedgehog and Notch signaling pathway in cancer.

Xia R, Xu M, Yang J, Ma X Mol Biomed. 2022; 3(1):44.

PMID: 36517618 PMC: 9751255. DOI: 10.1186/s43556-022-00099-8.

Targeting IKKα kinase to prevent tumor progression and therapy resistance.

Colomer C, Pecharroman I, Bigas A, Espinosa L Cancer Drug Resist. 2022; 3(3):482-490.

PMID: 35582445 PMC: 8992499. DOI: 10.20517/cdr.2019.104.

Notch signaling pathway: architecture, disease, and therapeutics.

Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K Signal Transduct Target Ther. 2022; 7(1):95.

PMID: 35332121 PMC: 8948217. DOI: 10.1038/s41392-022-00934-y.

References

Gasparian A, Yao Y, Kowalczyk D, Lyakh L, Karseladze A, Slaga T . The role of IKK in constitutive activation of NF-kappaB transcription factor in prostate carcinoma cells. J Cell Sci. 2002; 115(Pt 1):141-51. DOI: 10.1242/jcs.115.1.141. View

Krappmann D, Scheidereit C . A pervasive role of ubiquitin conjugation in activation and termination of IkappaB kinase pathways. EMBO Rep. 2005; 6(4):321-6. PMC: 1299290. DOI: 10.1038/sj.embor.7400380. View

Kawamata S, Du C, Li K, Lavau C . Overexpression of the Notch target genes Hes in vivo induces lymphoid and myeloid alterations. Oncogene. 2002; 21(24):3855-63. DOI: 10.1038/sj.onc.1205487. View

Suh J, Payvandi F, Edelstein L, Amenta P, Zong W, Gelinas C . Mechanisms of constitutive NF-kappaB activation in human prostate cancer cells. Prostate. 2002; 52(3):183-200. DOI: 10.1002/pros.10082. View

Hermanson O, Jepsen K, Rosenfeld M . N-CoR controls differentiation of neural stem cells into astrocytes. Nature. 2002; 419(6910):934-9. DOI: 10.1038/nature01156. View

Gilmore T, Kalaitzidis D, Starczynowski D . Rel/NF-kappa B/I kappa B signal transduction in the generation and treatment of human cancer. Cancer Lett. 2002; 181(1):1-9. DOI: 10.1016/s0304-3835(01)00795-9. View

Scaife C, Kuang J, Wills J, Trowbridge D, Gray P, Manning B . Nuclear factor kappaB inhibitors induce adhesion-dependent colon cancer apoptosis: implications for metastasis. Cancer Res. 2002; 62(23):6870-8. View

Kuroda K, Tani S, Tamura K, Minoguchi S, Kurooka H, Honjo T . Delta-induced Notch signaling mediated by RBP-J inhibits MyoD expression and myogenesis. J Biol Chem. 1999; 274(11):7238-44. DOI: 10.1074/jbc.274.11.7238. View

Park K, Krishnan V, OMalley B, Yamamoto Y, Gaynor R . Formation of an IKKalpha-dependent transcription complex is required for estrogen receptor-mediated gene activation. Mol Cell. 2005; 18(1):71-82. DOI: 10.1016/j.molcel.2005.03.006. View

10.

Song L, Zlobin A, Ghoshal P, Zhang Q, Houde C, Weijzen S . Alteration of SMRT tumor suppressor function in transformed non-Hodgkin lymphomas. Cancer Res. 2005; 65(11):4554-61. DOI: 10.1158/0008-5472.CAN-04-4108. View

11.

Cuevas I, Slocum A, Jun P, Costello J, Bollen A, Riggins G . Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res. 2005; 65(12):5070-5. DOI: 10.1158/0008-5472.CAN-05-0240. View

12.

van Es J, van Gijn M, Riccio O, van den Born M, Vooijs M, Begthel H . Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature. 2005; 435(7044):959-63. DOI: 10.1038/nature03659. View

13.

Fre S, Huyghe M, Mourikis P, Robine S, Louvard D, Artavanis-Tsakonas S . Notch signals control the fate of immature progenitor cells in the intestine. Nature. 2005; 435(7044):964-8. DOI: 10.1038/nature03589. View

14.

Jorda M, Olmeda D, Vinyals A, Valero E, Cubillo E, Llorens A . Upregulation of MMP-9 in MDCK epithelial cell line in response to expression of the Snail transcription factor. J Cell Sci. 2005; 118(Pt 15):3371-85. DOI: 10.1242/jcs.02465. View

15.

Hoberg J, Popko A, Ramsey C, Mayo M . IkappaB kinase alpha-mediated derepression of SMRT potentiates acetylation of RelA/p65 by p300. Mol Cell Biol. 2005; 26(2):457-71. PMC: 1346914. DOI: 10.1128/MCB.26.2.457-471.2006. View

16.

Leong K, Karsan A . Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2005; 107(6):2223-33. DOI: 10.1182/blood-2005-08-3329. View

17.

Karin M . Nuclear factor-kappaB in cancer development and progression. Nature. 2006; 441(7092):431-6. DOI: 10.1038/nature04870. View

18.

Yamamoto Y, Verma U, Prajapati S, Kwak Y, Gaynor R . Histone H3 phosphorylation by IKK-alpha is critical for cytokine-induced gene expression. Nature. 2003; 423(6940):655-9. DOI: 10.1038/nature01576. View

19.

Anest V, Hanson J, Cogswell P, Steinbrecher K, Strahl B, Baldwin A . A nucleosomal function for IkappaB kinase-alpha in NF-kappaB-dependent gene expression. Nature. 2003; 423(6940):659-63. DOI: 10.1038/nature01648. View

20.

Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A . Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem. 2003; 278(34):32227-35. DOI: 10.1074/jbc.M304001200. View