Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode

Abstract

The role of the transcription factor NF-κB in shaping the cancer microenvironment is becoming increasingly clear. Inflammation alters the activity of enzymes that modulate NF-κB function, and causes extensive changes in genomic chromatin that ultimately drastically alter cell-specific gene expression. NF-κB regulates the expression of cytokines and adhesion factors that control interactions among adjacent cells. As such, NF-κB fine tunes tissue cellular composition, as well as tissues' interactions with the immune system. Therefore, NF-κB changes the cell response to hormones and to contact with neighboring cells. Activating NF-κB confers transcriptional and phenotypic plasticity to a cell and thereby enables profound local changes in tissue function and composition. Research suggests that the regulation of NF-κB target genes is specifically altered in cancer. Such alterations occur not only due to mutations of NF-κB regulatory proteins, but also because of changes in the activity of specific proteostatic modules and metabolic pathways. This article describes the molecular mode of NF-κB regulation with a few characteristic examples of target genes.

Keywords: Cytokine; IL-6; IL-8/CXCL8; MUC1; NF-κB; TNFα; chemokine; mucin.

1

(A) Tissue response to internal or external insult followed by the activation of different cell types based on experimental evidence. The different cell types activated include several types of leukocytes (LC), resident macrophages (F), groups of resident cells in apoptosis (AC), and circulating components of the immune system migrating in successive waves (1-3). Selected groups of resident cells, such as epithelial cells (EC), undergo dedifferentiation into mesenchymal cells (MC) and re-epithelialization. Several mediators of immunosuppression are expressed. The immune response subsides, some leukocytes undergo apoptotic death (AL), and tissue function resumes (4-6). Accumulating data from molecular studies suggest that this succession of events is regulated by a chain of changes in the activity of sequence-specific transcription factors. In particular, factors that interact with Rel family proteins alter the gene selection activated by the Rel-domain proteins. This occurrence results in cell-specific patterns of gene expression and determines the function of each cell type during inflammation. (B) Simplified view of transcriptional regulation. Normally, transcription factor complex (i) is produced during inflammation, whereas complex (ii) appears during inflammatory resolution. After complex (ii) resolves, chromatin returns to its basal state, and the cell expresses genes depending on its typical function in the tissue. The cell is then prepared to induce complex (i) formation upon inflammatory stimulation. In cancer, pro- and anti-inflammatory mechanisms may be activated. The cancer cell may survive this occurrence by increasing the activity of intracellular turnover systems. Under the simultaneous expression of pro- and anti-inflammatory genes, a cancer cell is endowed with survival mechanisms under inflammation and sends mixed signals to its microenvironment.

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Interaction between transcription factors NF-κB and AP-1, which bind to their respective DNA target sequences and facilitate chromatin remodeling. In the nucleus, NF-κB binds to cognate sites and synergistically interacts with proteins to redistribute chromatin remodeling complexes on chromosomal DNA. This change affects the cellular developmental fate by altering protein occupancy in the proximal and distal gene regulatory regions in a cell-specific and gene-specific fashion.

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Genomic locus of the MUC1 gene on human chromosome 1. (A) The locus contains DNA binding sites for the RelA subunit of NF-κB. (B) NF-κB binding sites increase in abundance when transcription factors that interact with NF-κB bind to their cognate DNA target sites, and thereby recruit NF-κB to the locus. These transcription factors change in activity during inflammation. The product of the MUC1 gene is the protein MUC1, which participates in cytokine gene regulation and tissue homeostasis.