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Review
. 2022 Aug 15;41(1):248.
doi: 10.1186/s13046-022-02461-8.

The diverse functions of FAT1 in cancer progression: good, bad, or ugly?

Zhuo Georgia Chen  1 , Nabil F Saba  1 , Yong Teng  2
Affiliations
Review

The diverse functions of FAT1 in cancer progression: good, bad, or ugly?

Zhuo Georgia Chen et al. J Exp Clin Cancer Res. .

Abstract

FAT atypical cadherin 1 (FAT1) is among the most frequently mutated genes in many types of cancer. Its highest mutation rate is found in head and neck squamous cell carcinoma (HNSCC), in which FAT1 is the second most frequently mutated gene. Thus, FAT1 has great potential to serve as a target or prognostic biomarker in cancer treatment. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular "brake" on mitochondrial respiration and acts as a receptor for a signaling pathway regulating cell-cell contact interaction and planar cell polarity. In many cancers, loss of FAT1 function promotes epithelial-mesenchymal transition (EMT) and the formation of cancer initiation/stem-like cells. However, in some types of cancer, overexpression of FAT1 leads to EMT. The roles of FAT1 in cancer progression, which seems to be cancer-type specific, have not been clarified. To further study the function of FAT1 in cancers, this review summarizes recent relevant literature regarding this protein. In addition to phenotypic alterations due to FAT1 mutations, several signaling pathways and tumor immune systems known or proposed to be regulated by this protein are presented. The potential impact of detecting or targeting FAT1 mutations on cancer treatment is also prospectively discussed.

Keywords: Cancer progression; FAT1; Gene mutations; Signaling regulatory network; Targeted treatment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Human FAT1 protein structure
Fig. 2
Fig. 2
Major signaling pathways affected by mutated FAT1. A Wnt/β-catenin signaling pathway: FAT1 can bind to β-catenin. Mutated FAT1 releases β-catenin from proteasomal degradation complex, which enhances the nuclear translocation and transcriptional activity of β-catenin. B Hippo/YAP1 activation and receptor tyrosine kinase (RTK) signaling pathways: Mutated FAT1 releases YAP1 from Hippo complex and activates it as a transcription factor. Mutated FAT1 also enhances HER3 activation and IRS1 expression, which may contribute to activation of multiple RTK signaling pathways. A potential link between YAP1 and ERBB signaling may be due to an autocrine loop through their ligand EGF and NRGs
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