N-linked glycosylation is essential for anti-tumor activities of KIAA1324 in gastric canceropen access
- Authors
- Yun, Rebecca; Hong, Eunji; Kim, Junil; Park, Bora; Kim, Staci Jakyong; Lee, Bona; Song, Yong Sang; Kim, Seong-Jin; Park, Sujin; Kang, Jin Muk
- Issue Date
- Aug-2023
- Publisher
- SPRINGERNATURE
- Citation
- CELL DEATH & DISEASE, v.14, no.8
- Journal Title
- CELL DEATH & DISEASE
- Volume
- 14
- Number
- 8
- URI
- https://scholarworks.bwise.kr/ssu/handle/2018.sw.ssu/44359
- DOI
- 10.1038/s41419-023-06083-6
- ISSN
- 2041-4889
- 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.
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