Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Apr 17;6(2):44.
doi: 10.3390/biomedicines6020044.

Subunit-Specific Role of NF-κB in Cancer

Barbara Kaltschmidt  1 , Johannes F W Greiner  2 , Hussamadin M Kadhim  3 , Christian Kaltschmidt  4
Affiliations
Review

Subunit-Specific Role of NF-κB in Cancer

Barbara Kaltschmidt et al. Biomedicines. .

Abstract

The transcription factor NF-κB is a key player in inflammation, cancer development, and progression. NF-κB stimulates cell proliferation, prevents apoptosis, and could promote tumor angiogenesis as well as metastasis. Extending the commonly accepted role of NF-κB in cancer formation and progression, different NF-κB subunits have been shown to be active and of particular importance in distinct types of cancer. Here, we summarize overexpression data of the NF-κB subunits RELA, RELB, and c-REL (referring to the v-REL, which is the oncogene of Reticuloendotheliosis virus strain T) as well as of their upstream kinase inhibitor, namely inhibitor of κB kinases (IKK), in different human cancers, assessed by database mining. These data argue against a universal mechanism of cancer-mediated activation of NF-κB, and suggest a much more elaborated mode of NF-κB regulation, indicating a tumor type-specific upregulation of the NF-κB subunits. We further discuss recent findings showing the diverse roles of NF-κB signaling in cancer development and metastasis in a subunit-specific manner, emphasizing their specific transcriptional activity and the role of autoregulation. While non-canonical NF-κB RELB signaling is described to be mostly present in hematological cancers, solid cancers reveal constitutive canonical NF-κB RELA or c-REL activity. Providing a linkage to cancer therapy, we discuss the recently described pivotal role of NF-κB c-REL in regulating cancer-targeting immune responses. In addition, current strategies and ongoing clinical trials are summarized, which utilize genome editing or drugs to inhibit the NF-κB subunits for cancer treatment.

Keywords: NF-κB; RELA; RELB; Treg; cREL; cancer; gene expression; inflammation; transformation; tumor; tumor necrosis factor.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
NF-κB and autoregulation of NF-κB subunits in cancer. (A) Schematic view of the NF-κB-family ([11]). (B) Principal mechanisms causing overexpression/activation of NF-κB as well as the cellular effects of NF-κB acitivity leading to cancer development and progression. RHD: REL homology domain, TAD: transactivation domain. (C) The promoters of NF-κB subunits RELA, RELB, and c-REL contain various κB sites enabling autoregulation of NF-κB in cancer. Promoter analysis was done as described in [12]. Briefly, sequences of promoter regions (3000 bp downstream and 100 bp upstream of the respective ATG) of interest were taken from Eukaryotic Promoter Database (epd.vital-ti.ch) for Homo sapiens. The binding sites for the gene of interest in the chosen promoter sequence were looked up using the JASPAR Tool [13]) with a relative score threshold of 85%.
Figure 2
Figure 2
Graphical overview on the differential roles of NF-κB subunits and their transcriptional activity in distinct types of cancer and in regulatory T cells. While non-canonical signaling is mostly present in hematological cancer, solid cancer shows predominantly canonical signaling via p50/RELA or p50/cREL. In addition, CRISPR/Cas-mediated double knockout (KO) of IKK1/2 was recently shown to result in increased sensitity to TNF-α-mediated cell death [38]. In regulatory T cells (Tregs), activation of RELA/cREL results in distinct target gene expression leading to active Tregs inhibiting effector T cells (Teff), which infiltrate the tumor [11,12,52,55,56,57,58].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sen R., Baltimore D. Inducibility of kappa immunoglobulin enhancer-binding protein NF-kappaB by a posttranslational mechanism. Cell. 1986;47:921–928. doi: 10.1016/0092-8674(86)90807-X. - DOI - PubMed
    1. Sen R., Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46:705–716. doi: 10.1016/0092-8674(86)90346-6. - DOI - PubMed
    1. Perkins N.D. Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat. Rev. Mol. Cell Biol. 2007;8:49–62. doi: 10.1038/nrm2083. - DOI - PubMed
    1. Kaltschmidt B., Kaltschmidt C. NF-kappaB in the nervous system. Cold Spring Harb. Perspect. Biol. 2009;1:a001271. doi: 10.1101/cshperspect.a001271. - DOI - PMC - PubMed
    1. Kaltschmidt B., Kaltschmidt C. NF-kappaB in long-term memory and structural plasticity in the adult mammalian brain. Front. Mol. Neurosci. 2015;8:69. doi: 10.3389/fnmol.2015.00069. - DOI - PMC - PubMed

LinkOut - more resources