Abstract
Primary or acquired drug resistance accounts for the failure of chemotherapy and cancer recurrence in esophageal squamous cell carcinoma (ESCC). However, the aberrant mechanisms driving drug resistance are not fully understood in ESCC. In our previous study, FAT Atypical Cadherin 1 (FAT1) was found to inhibit the epithelial–mesenchymal transition (EMT) process in ESCC. EMT plays a critical role in the development of drug resistance in multiple cancer types. Besides, it equips cancer cells with cancer stem cell (CSC)-like characters that also are associated with chemotherapy resistance. Whether FAT1 regulates the stemness or drug resistance of ESCC cells is worth being explored. Here we found that FAT1 was downregulated in ESCC spheres and negatively correlated with stemness-associated markers including ALDH1A1 and KLF4. Knocking down FAT1 enhanced the sphere-forming ability, resistance to cisplatin and drug efflux of ESCC cells. Additionally, FAT1 knockdown upregulated the expression of drug resistance-related gene ABCC3. Furtherly, we found FAT1 knockdown induced the translocation of β-catenin into nucleus and enhanced its transcriptional activity. The result of ChIP showed that β-catenin was enriched in ABCC3 promoter. Furthermore, β-catenin promoted expression of ABCC3. In conclusion, FAT1 knockdown might enhance the stemness and ABCC3-related cisplatin resistance of ESCC cells via Wnt/β-catenin signaling pathway. FAT1 and its downstream gene ABCC3 might be potential targets for overcoming chemoresistance in ESCC.
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The analyzed data sets generated during the present study are available from the corresponding author on reasonable request.
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This work was supported by funding from the National Natural Science Foundation of China (81802825 to X.H.).
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Conceptualization: XC, XH, YZ; Methodology: CS; Validation: CS, YZ; Formal analysis: PK, HZ; Investigation: HZ; Resources: XH; Data curation: LZ, CS; Writing original draft: YZ; Writing review and editing: YW; Supervision: PK, XC; Project administration: XH, XC; Funding acquisition: XH. All authors have contributed significantly and approved the submitted version.
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11010_2022_4475_MOESM1_ESM.tif
Supplementary file1 (TIF 1675 kb) Fig. Supplement FAT1 expression is different in the four groups. A–D FAT1 expression was different in the four groups for 277 patients across cancer types, 115 patients with pan-SCC, 42 patients with HNSC and 57 patients with CSCC. E The relationship between FAT1 and ABCC3 by analyzing GSE53625 data set. F The relationship between CTNNB1 and ABCC3 by analyzing GSE53625 data set
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Zhai, Y., Shan, C., Zhang, H. et al. FAT1 downregulation enhances stemness and cisplatin resistance in esophageal squamous cell carcinoma. Mol Cell Biochem 477, 2689–2702 (2022). https://doi.org/10.1007/s11010-022-04475-4
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DOI: https://doi.org/10.1007/s11010-022-04475-4