Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors.
NF-kappaB (RelA) is constitutively active in many cancers, where it upregulates antiapoptotic and other oncogenic genes. While proinflammatory stimulus-induced NF-kappaB activation involves IKK-dependent nuclear translocation, mechanisms for maintaining constitutive NF-kappaB activity in tumors have not been elucidated. We show here that maintenance of NF-kappaB activity in tumors requires Stat3, which is also frequently constitutively activated in cancer. Stat3 prolongs NF-kappaB nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-kappaB nuclear export. Stat3-mediated maintenance of NF-kappaB activity occurs in both cancer cells and tumor-associated hematopoietic cells. Both murine and human cancers display highly acetylated RelA, which is associated with Stat3 activity. This Stat3/NF-kappaB interaction is thus central to both the transformed and nontransformed elements in tumors.
Lee
Heehyoung
H
Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
Herrmann
Andreas
A
Deng
Jie-Hui
JH
Kujawski
Maciej
M
Niu
Guilian
G
Li
Zhiwei
Z
Forman
Steve
S
Jove
Richard
R
Pardoll
Drew M
DM
Yu
Hua
H
D000107:Acetylation; D021581:Active Transport, Cell Nucleus; D000818:Animals; D024202:Electrophoretic Mobility Shift Assay; D005455:Fluorescent Antibody Technique; D006413:Hematopoietic System / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
D006655:Histone Deacetylases; D019426:Integrases; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C045073:Cre recombinase