N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer
Abstract KIAA1324 is a transmembrane protein largely reported as a tumor suppressor and favorable prognosis marker in various cancers, including gastric cancer. In this study, we report the role of N-linked glycosylation in KIAA1324 as a functional post-translational modification (PTM). Loss of N-li...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06083-6 |
| _version_ | 1797736410219806720 |
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| author | Rebecca Yun Eunji Hong Junil Kim Bora Park Staci Jakyong Kim Bona Lee Yong Sang Song Seong-Jin Kim Sujin Park Jin Muk Kang |
| author_facet | Rebecca Yun Eunji Hong Junil Kim Bora Park Staci Jakyong Kim Bona Lee Yong Sang Song Seong-Jin Kim Sujin Park Jin Muk Kang |
| author_sort | Rebecca Yun |
| collection | DOAJ |
| description | Abstract KIAA1324 is a transmembrane protein largely reported as a tumor suppressor and favorable prognosis marker in various cancers, including gastric cancer. In this study, we report the role of N-linked glycosylation in KIAA1324 as a functional post-translational modification (PTM). Loss of N-linked glycosylation eliminated the potential of KIAA1324 to suppress cancer cell proliferation and migration. Furthermore, we demonstrated that KIAA1324 undergoes fucosylation, a modification of the N-glycan mediated by fucosyltransferase, and inhibition of fucosylation also significantly suppressed KIAA1324-induced cell growth inhibition and apoptosis of gastric cancer cells. In addition, KIAA1324-mediated apoptosis and tumor regression were inhibited by the loss of N-linked glycosylation. RNA sequencing (RNAseq) analysis revealed that genes most relevant to the apoptosis and cell cycle arrest pathways were modulated by KIAA1324 with the N-linked glycosylation, and Gene Regulatory Network (GRN) analysis suggested novel targets of KIAA1324 for anti-tumor effects in the transcription level. The N-linked glycosylation blockade decreased protein stability through rapid proteasomal degradation. The non-glycosylated mutant also showed altered localization and lost apoptotic activity that inhibits the interaction between GRP78 and caspase 7. These data demonstrate that N-linked glycosylation of KIAA1324 is essential for the suppressive role of KIAA1324 protein in gastric cancer progression and indicates that KIAA1324 may have anti-tumor effects by targeting cancer-related genes with N-linked glycosylation. In conclusion, our study suggests the PTM of KIAA1324 including N-linked glycosylation and fucosylation is a necessary factor to consider for cancer prognosis and therapy improvement. |
| first_indexed | 2024-03-12T13:13:25Z |
| format | Article |
| id | doaj.art-689e484b1fc54aaba7ba76e6d22e7e69 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T13:13:25Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-689e484b1fc54aaba7ba76e6d22e7e692023-08-27T11:30:05ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811210.1038/s41419-023-06083-6N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancerRebecca Yun0Eunji Hong1Junil Kim2Bora Park3Staci Jakyong Kim4Bona Lee5Yong Sang Song6Seong-Jin Kim7Sujin Park8Jin Muk Kang9GILO Institute, GILO FoundationGILO Institute, GILO FoundationSchool of Systems Biomedical Science, Soongsil UniversityWellSpan York Hospital Family Medicine Residency ProgramInternational Institute for Integrative Sleep Medicine, University of TsukubaCase Western Reserve University School of MedicineInterdisciplinary Program in Cancer Biology, Seoul National University, Gwanak-guGILO Institute, GILO FoundationGILO Institute, GILO FoundationDepartment of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical CenterAbstract KIAA1324 is a transmembrane protein largely reported as a tumor suppressor and favorable prognosis marker in various cancers, including gastric cancer. In this study, we report the role of N-linked glycosylation in KIAA1324 as a functional post-translational modification (PTM). Loss of N-linked glycosylation eliminated the potential of KIAA1324 to suppress cancer cell proliferation and migration. Furthermore, we demonstrated that KIAA1324 undergoes fucosylation, a modification of the N-glycan mediated by fucosyltransferase, and inhibition of fucosylation also significantly suppressed KIAA1324-induced cell growth inhibition and apoptosis of gastric cancer cells. In addition, KIAA1324-mediated apoptosis and tumor regression were inhibited by the loss of N-linked glycosylation. RNA sequencing (RNAseq) analysis revealed that genes most relevant to the apoptosis and cell cycle arrest pathways were modulated by KIAA1324 with the N-linked glycosylation, and Gene Regulatory Network (GRN) analysis suggested novel targets of KIAA1324 for anti-tumor effects in the transcription level. The N-linked glycosylation blockade decreased protein stability through rapid proteasomal degradation. The non-glycosylated mutant also showed altered localization and lost apoptotic activity that inhibits the interaction between GRP78 and caspase 7. These data demonstrate that N-linked glycosylation of KIAA1324 is essential for the suppressive role of KIAA1324 protein in gastric cancer progression and indicates that KIAA1324 may have anti-tumor effects by targeting cancer-related genes with N-linked glycosylation. In conclusion, our study suggests the PTM of KIAA1324 including N-linked glycosylation and fucosylation is a necessary factor to consider for cancer prognosis and therapy improvement.https://doi.org/10.1038/s41419-023-06083-6 |
| spellingShingle | Rebecca Yun Eunji Hong Junil Kim Bora Park Staci Jakyong Kim Bona Lee Yong Sang Song Seong-Jin Kim Sujin Park Jin Muk Kang N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer Cell Death and Disease |
| title | N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer |
| title_full | N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer |
| title_fullStr | N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer |
| title_full_unstemmed | N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer |
| title_short | N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric cancer |
| title_sort | n linked glycosylation is essential for anti tumor activities of kiaa1324 in gastric cancer |
| url | https://doi.org/10.1038/s41419-023-06083-6 |
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