Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Abstract

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

Keywords: FOX; Wnt; beta-catenin; forkhead; transcription factors.

Figure 1

Overview of the canonical Wnt/β-catenin signaling pathway. Hallmark alterations in Wnt pathway activity in Wnt-dependent cancer cells are indicated on the right.

Figure 2

Gene expression changes of FOX transcription factors in selected cancers. Data sources are indicated in the data availability statement at the end of the manuscript. Classification of genes as Wnt pathway activators or inhibitors is based on the literature, see Table 1. Only data points with >2-fold change in expression and an adjusted p value < 10⁻⁵⁰ are labeled.

Figure 3

Proposed mode of action of selected FOX transcription factors in the Wnt signaling pathway.

Figure 4

Schematic representation of known FOX protein/β-catenin interactions. Solid grey lines indicate experimentally mapped binding domains. All proteins are shown in N-to-C-terminal orientation. FOX, (DNA-binding) forkhead box; HMG, (DNA-binding) high mobility group box.