Abstract
The WASF3 gene facilitates the metastatic phenotype, and its inactivation leads to suppression of invasion and metastasis regardless of the genetic background of the cancer cell. This reliance on WASF3 to facilitate metastasis suggests that targeting its function could serve as an effective strategy to suppress metastasis. WASF3 stability and function are regulated by the WASF Regulatory Complex (WRC) of proteins, particularly CYFIP1 and NCKAP1. Knockdown of these proteins in vitro leads to disruption of the WRC and suppression of invasion. We have used mouse xenograft models of breast cancer metastasis to assess whether targeting the WRC complex suppresses metastasis in vivo. Stapled peptides targeting the WASF3-CYFIP1 interface (WAHM1) and the CYFIP1-NCKAP1 interface (WANT3) suppress the development of lung and liver metastases. Targeting these critical protein-protein interactions, therefore, could potentially be developed into a therapeutic strategy to control cancer cell invasion and metastasis.
Highlights
The majority of cancer deaths (>90%) result from consequences of metastatic spread,[1] and so targeting this aspect of disease progression could have a significant impact on survival
Many genes have been implicated in the development and promotion of the metastatic phenotype,[2] and we have previously demonstrated a central role for the WASF3 gene in this process.[3,4]
In the cohort treated with WAHM1 peptides, there was a significant reduction in the observed extent of dissemination of tumor cells (Figure 1B), suggesting reduced metastasis
Summary
The majority of cancer deaths (>90%) result from consequences of metastatic spread,[1] and so targeting this aspect of disease progression could have a significant impact on survival. WASF3 promotes expression of genes involved in epithelial to mesenchymal transition, such as ZEB111 and members of the matrix metalloproteinase (MMP) family,[4] through a signaling pathway that downregulates the KISS1 metastasis suppressor gene leading to activation of nuclear factor κB.[12] WASF3 is activated in response to hypoxia,[13] as well as growth factor and cytokine stimulation of JAK2/STAT3 signaling.[10] Under these conditions, WASF3 is recruited to the membrane and interacts with RAC, leading to relaxation of inhibitory protein complexes and allowing recruitment of actin monomers to facilitate actin polymerization.[14] WASF3 is held in an inactive, autoregulated form in unstimulated cells through engagement of a series of proteins including CYFIP1, NCKAP1, BRK1, and ABI1 through interactions with its N-terminus,[15,16,17] forming the so-called WASF Regulatory Complex (WRC) The presence of this complex distinguishes the WASF proteins from other members of the superfamily, such as WASP and NWASP, which do not contain this motif and do not bind to RAC.[18]
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