An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling
Tao, Bolin; Wang, Zhenning; Wang, Xuanyi; Song, Aixia; Liu, Jiaxian; Wang, Jianan; Zhang, Qin; Chen, Zhaolin; Wang, Zixian; Xu, Wenjie; Sun, Menghong; Wang, Yanong; Zhang, Ping; Xu, Tao; Wei, Gong-Hong; Chen, Fei Xavier; Wang, Mengyun (2025-02-25)
American Society for Clinical Investigation
25.02.2025
Tao, B., Wang, Z., Wang, X., Song, A., Liu, J., Wang, J., Zhang, Q., Chen, Z., Wang, Z., Xu, W., Sun, M., Wang, Y., Zhang, P., Xu, T., Wei, G.-H., Chen, F. X., & Wang, M. (2025). An inherited predisposition allele promotes gastric cancer via enhancing deubiquitination-mediated activation of epithelial-to-mesenchymal transition signaling. Journal of Clinical Investigation, 135(8), e179617. https://doi.org/10.1172/JCI179617
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Copyright © 2025 American Society for Clinical Investigation. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
Copyright © 2025 American Society for Clinical Investigation. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
https://creativecommons.org/licenses/by/4.0/
Julkaisun pysyvä osoite on
https://urn.fi/URN:NBN:fi:oulu-202502261846
https://urn.fi/URN:NBN:fi:oulu-202502261846
Tiivistelmä
Abstract
Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the single nucleotide polymorphism (SNP) rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC (OR = 0.78, P = 0.015). Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients.
Genome-wide human genetic studies have identified inherited cis-regulatory loci variants that predispose to cancers. However, the mechanisms by which these germline variants influence cancer progression, particularly through gene expression and proteostasis control, remain unclear. By analyzing genomic data from a gastric cancer (GC) case-control study (2,117 individuals), focusing on the ubiquitin-specific protease (USP) family, we identify the single nucleotide polymorphism (SNP) rs72856331 (G>A) in the promoter region of the proto-oncogene USP47 as a putative susceptibility allele for GC (OR = 0.78, P = 0.015). Mechanistically, the risk allele G is associated with enhanced USP47 expression, mediated by altered recruitment of the transcription factor GLI3 and changes in the epigenetic status at promoter. CRISPR/Cas9-mediated single-nucleotide conversion into risk allele G results in increased GLI3 binding and subsequent USP47 upregulation. The depletion of GLI3 results in a reduction of cancer-related phenotypes, similar to those observed following USP47 knockdown. Furthermore, we identify Snai1 as a deubiquitination target of USP47, explaining USP47-dependent activation of epithelial-mesenchymal transition pathway and tumor progression. Our findings identify an important genetic predisposition that implicates the perturbation of transcription and proteostasis programs in GC, offering insights into prevention and therapeutic strategies for genetically stratified patients.
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