Understanding the role of ETS-mediated gene regulation in complex biological processes

Abstract

Ets factors are members of one of the largest families of evolutionarily conserved transcription factors, regulating critical functions in normal cell homeostasis, which when perturbed contribute to tumor progression. The well-documented alterations in ETS factor expression and function during cancer progression result in pleiotropic effects manifested by the downstream effect on their target genes. Multiple ETS factors bind to the same regulatory sites present on target genes, suggesting redundant or competitive functions. The anti- and prometastatic signatures obtained by examining specific ETS regulatory networks will significantly improve our ability to accurately predict tumor progression and advance our understanding of gene regulation in cancer. Coordination of multiple ETS gene functions also mediates interactions between tumor and stromal cells and thus contributes to the cancer phenotype. As such, these new insights may provide a novel view of the ETS gene family as well as a focal point for studying the complex biological control involved in tumor progression. One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such an understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection, as well as better diagnosis and staging of disease; (2) detection of minimal residual disease recurrences and evaluation of response to therapy; (3) prevention; and (4) novel treatment strategies. Increased understanding of ETS-regulated biological pathways will directly impact these areas.

Keywords: Cancer; ETS; Regulation; Target genes; Transcription factors.

Figure 1.1

The human ETS family of transcription factors. The main structural organization of each human ETS protein by subfamily (see Table 1.1) is depicted. The ETS and Pointed domains are indicated.

Figure 1.2

ETS factors regulate the expression of genes associated with cancer progression. Dysregulated ETS factor function leads to the altered expression of multiple target genes that are known to play critical roles in many of the processes required for cancer progression. While each of the target genes highlighted has functional EBS(s) in their regulatory regions, the role and relative affinities of specific ETS factors have only been examined in a limited subset.

Figure 1.3

Hypothetical model of the ETS regulatory network in cancer. See text for details.

Figure 1.4

Therapeutic strategies for targeting ETS factor biology. Strategies have included directly inhibiting the promoter of oncogenic ETS factors; directly targeting specific ETS factor mRNA to prevent the expression of their target genes; directly targeting the ETS protein itself or indirectly targeting ETS responsive promoters of transcriptional target genes. See text for details. RNAi, RNA interference; miRNA, microRNA; GA, gambogic acid nanoparticles; ?, direct versus indirect effect; DN, dominant negative; ETS, E26 transforming sequence; ODN, decoy oligonucleotide; SMI, small-molecule inhibitor; TFO, triplex-forming oligonucleotide.