Persistently-activated Stat3 maintains constitutive NF-κB activity in tumors

By Heehyoung Lee, A. Herrmann, Jiehui Deng, M. Kujawski, G. Niu, Zhiwei Li, Steve Forman, R. Jove, D. Pardoll, Hua Yu. Cancer Cell, 2009

695 citations recorded by the source corpus.

SUMMARY NF-κB (RelA) is constitutively active in many cancers where it up-regulates anti-apoptotic and other oncogenic genes. While proinflammatory stimulus-induced NF-κB activation involves IKK-dependent nuclear translocation, mechanisms for maintaining constitutive NF-κB activity in tumors have not been elucidated. We show here that maintenance of NF-κB activity in tumors requires Stat3 that is also frequently constitutively activated in cancer. Stat3 prolongs NF-κB nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-κB nuclear export. Stat3-mediated maintenance of NF-κB activity occurs both in cancer cells and in tumor-associated hematopoietic cells. Both murine and human cancers display highly acetylated RelA, which is associated with Stat3 activity. This Stat3/NF-κB interaction is thus central to both the transformed and nontransformed elements in tumors.

Subfields: Cancer Research, Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/832946521186e8a1ddbf8d1f41a7ebb22275269d

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Citations in the corpus

Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function (2010, background): “Moreover, transcription factors can modulate the activity of each other, as was shown, for instance, for Stat3 and NF-κB [70] [71].”
STATs in cancer inflammation and immunity: a leading role for STAT3 (2009, neutral): “, it is not surprising that signalling by various STATs, particularly STAT3, is highly interconnected with NF-κB signallin”
Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. (2014, background): “STAT3 can directly interact with nuclear factor, NF-κB familymember RelA, through acetyltransferase p300-mediated acetylation, trapping it in the nucleus and thereby contributing to constitutive NF-κB activation in tumor-associated hematopoietic cells and various malignancies [156].”
Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. (2009, neutral): “requires STAT3 [23].”
Dangerous liaisons: STAT3 and NF-κB collaboration and crosstalk in cancer (2009, background): “Another mechanism that fine tunes of STAT3 activity, is its reversible acetylation [38], which also affects the activity of NF-kB family members [39].”
The JAK/STAT signaling pathway: from bench to clinic (2021, background): “In cancer cells and tumor-related haematopoietic cells, constitutively activated STAT3 drives the hyperacetylation of RelA, mediated by interactions with p300, thereby prolonging NF-κB nuclear retention and promoting the activation of NF-κB.202 In addition, cyclooxygenase-2, IL-17, IL-21, and IL-23 ”
IL-6 in inflammation, autoimmunity and cancer (2020, background): “For example, STAT3 prolongs NF-κ B nuclear retention through acetyltransferase p300-mediated RelA acetylation, thereby interfering with NF-κ B nuclear export in both cancer cells and tumor-associated hematopoietic cells (277).”
The complexity of NF-κB signaling in inflammation and cancer (2013, background): “In addition, there is another level of regulation, as it has been shown that STAT3 can modify RelA post-translationally by recruitment of the acetyltransferase p300, mediating acetylation of NFκB and prolongation of its nuclear retention [111].”