GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells
Abstract The single nucleotide polymorphism (SNP) rs9679162 located on GALNT14 gene predicts therapeutic outcomes in patients with intermediate and advanced hepatocellular carcinoma (HCC), but the molecular mechanism remains unclear. Here, the associations between SNP genotypes, GALNT14 expression,...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-05419-y |
| _version_ | 1811318063428009984 |
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| author | Yu-De Chu Tan-Chi Fan Ming-Wei Lai Chau-Ting Yeh |
| author_facet | Yu-De Chu Tan-Chi Fan Ming-Wei Lai Chau-Ting Yeh |
| author_sort | Yu-De Chu |
| collection | DOAJ |
| description | Abstract The single nucleotide polymorphism (SNP) rs9679162 located on GALNT14 gene predicts therapeutic outcomes in patients with intermediate and advanced hepatocellular carcinoma (HCC), but the molecular mechanism remains unclear. Here, the associations between SNP genotypes, GALNT14 expression, and downstream molecular events were determined. A higher GALNT14 cancerous/noncancerous ratio was associated with the rs9679162-GG genotype, leading to an unfavorable postoperative prognosis. A novel exon-6-skipped GALNT14 mRNA variant was identified in patients carrying the rs9679162-TT genotype, which was associated with lower GALNT14 expression and favorable prognosis. Cell-based experiments showed that elevated levels of GALNT14 promoted HCC growth, migration, and resistance to anticancer drugs. Using a comparative lectin-capture glycoproteomic approach, PHB2 was identified as a substrate for GALNT14-mediated O-glycosylation. Site-directed mutagenesis experiments revealed that serine-161 (Ser161) was the O-glycosylation site. Further analysis showed that O-glycosylation of PHB2-Ser161 was required for the GALNT14-mediated growth-promoting phenotype. O-glycosylation of PHB2 was positively correlated with GALNT14 expression in HCC, resulting in increased interaction between PHB2 and IGFBP6, which in turn led to the activation of IGF1R-mediated signaling. In conclusion, the GALNT14-rs9679162 genotype was associated with differential expression levels of GALNT14 and the generation of a novel exon-6-skipped GALNT14 mRNA variant, which was associated with a favorable prognosis in HCC. The GALNT14/PHB2/IGF1R cascade modulated the growth, migration, and anticancer drug resistance of HCC cells, thereby opening the possibility of identifying new therapeutic targets against HCC. |
| first_indexed | 2024-04-13T12:19:12Z |
| format | Article |
| id | doaj.art-4fe5349a99bb40d58c95f4bc3674d74c |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-13T12:19:12Z |
| publishDate | 2022-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-4fe5349a99bb40d58c95f4bc3674d74c2022-12-22T02:47:16ZengNature Publishing GroupCell Death and Disease2041-48892022-11-01131111310.1038/s41419-022-05419-yGALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cellsYu-De Chu0Tan-Chi Fan1Ming-Wei Lai2Chau-Ting Yeh3Liver Research Center, Chang Gung Memorial HospitalInstitute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at LinkouLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalAbstract The single nucleotide polymorphism (SNP) rs9679162 located on GALNT14 gene predicts therapeutic outcomes in patients with intermediate and advanced hepatocellular carcinoma (HCC), but the molecular mechanism remains unclear. Here, the associations between SNP genotypes, GALNT14 expression, and downstream molecular events were determined. A higher GALNT14 cancerous/noncancerous ratio was associated with the rs9679162-GG genotype, leading to an unfavorable postoperative prognosis. A novel exon-6-skipped GALNT14 mRNA variant was identified in patients carrying the rs9679162-TT genotype, which was associated with lower GALNT14 expression and favorable prognosis. Cell-based experiments showed that elevated levels of GALNT14 promoted HCC growth, migration, and resistance to anticancer drugs. Using a comparative lectin-capture glycoproteomic approach, PHB2 was identified as a substrate for GALNT14-mediated O-glycosylation. Site-directed mutagenesis experiments revealed that serine-161 (Ser161) was the O-glycosylation site. Further analysis showed that O-glycosylation of PHB2-Ser161 was required for the GALNT14-mediated growth-promoting phenotype. O-glycosylation of PHB2 was positively correlated with GALNT14 expression in HCC, resulting in increased interaction between PHB2 and IGFBP6, which in turn led to the activation of IGF1R-mediated signaling. In conclusion, the GALNT14-rs9679162 genotype was associated with differential expression levels of GALNT14 and the generation of a novel exon-6-skipped GALNT14 mRNA variant, which was associated with a favorable prognosis in HCC. The GALNT14/PHB2/IGF1R cascade modulated the growth, migration, and anticancer drug resistance of HCC cells, thereby opening the possibility of identifying new therapeutic targets against HCC.https://doi.org/10.1038/s41419-022-05419-y |
| spellingShingle | Yu-De Chu Tan-Chi Fan Ming-Wei Lai Chau-Ting Yeh GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells Cell Death and Disease |
| title | GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells |
| title_full | GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells |
| title_fullStr | GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells |
| title_full_unstemmed | GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells |
| title_short | GALNT14-mediated O-glycosylation on PHB2 serine-161 enhances cell growth, migration and drug resistance by activating IGF1R cascade in hepatoma cells |
| title_sort | galnt14 mediated o glycosylation on phb2 serine 161 enhances cell growth migration and drug resistance by activating igf1r cascade in hepatoma cells |
| url | https://doi.org/10.1038/s41419-022-05419-y |
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