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Peer-reviewedCC BY-NC-ND 4.0Chinese Medical Journal

Asparagine-linked glycosyltransferase 6 deficiency suppresses tumorigenesis in clear cell renal cell carcinoma by regulating apoptosis and immunotherapy sensitivity

  • Zilian Cui1
  • Ning Wang2
  • Zonghai Liu3
  • Shaoan Chen1
  1. 1Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
  2. 2Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China
  3. 3Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021, China
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Abstract

Background:: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) with a poor prognosis in advanced stages. One of the major challenges in ccRCC treatment is the resistance to tyrosine kinase inhibitors or immune checkpoint inhibitors. Asparagine-linked glycosyltransferase 6 (ALG6) is a glycosyltransferase whose biological role in tumorigenesis remains largely unknown. Therefore, this study aims to investigate its function in ccRCC and its potential involvement in therapeutic resistance.

Methods:: We first analyzed 30 paired ccRCC and adjacent normal tissues from Shandong Provincial Hospital, correlating ALG6 expression with clinicopathological features (age, sex, tumor size, Tumor–Node–Metastasis [TNM] stage). In vitro, CCK-8, colony formation, and apoptosis assays were performed to assess the functional role of ALG6 in ccRCC cell lines. In vivo, a subcutaneous C57BL/6J mouse model and flow cytometry was used to evaluate the effect of ALG6 on the immune microenvironment and anti-PD-1 antibody sensitivity.

Results:: In this study, we found that ALG6 was significantly overexpressed in ccRCC. Elevated ALG6 expression was positively correlated with tumor size and TNM stage, but negatively associated with overall survival in patients with ccRCC. Functional experiments demonstrated that downregulation of endogenous ALG6 markedly suppressed ccRCC cell viability and promoted apoptosis both in vitro and in vivo. Mechanistically, knockdown of ALG6 triggered endoplasmic reticulum (ER) stress, as evidenced by the upregulation of glucose-regulated protein 78 (GRP78) and activation of C/EBP homologous protein (CHOP) in ccRCC cells. Notably, knockdown of ALG6 significantly reduced programmed cell death ligand 1 (PD-L1) expression by inhibiting PD-L1 glycosylation and promoting its ubiquitin-mediated degradation. Furthermore, in vivo experiments demonstrated that ALG6 depletion destabilized PD-L1, enhanced antitumor T-cell immunity, and improved the therapeutic efficacy of anti-PD-1 treatment.

Conclusions:: This study demonstrates that downregulation of ALG6 induces ER stress-mediated apoptosis and enhances antitumor immunity by regulating PD-L1 expression in ccRCC. These findings suggest that ALG6 may serve as a potential therapeutic target for ccRCC.

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Cite

BibTeXRIS
BibTeX
@article{cui2026asparaginelinked,
  title = {{Asparagine-linked glycosyltransferase 6 deficiency suppresses tumorigenesis in clear cell renal cell carcinoma by regulating apoptosis and immunotherapy sensitivity}},
  author = {Zilian Cui and Ning Wang and Zonghai Liu and Shaoan Chen},
  journal = {Chinese Medical Journal},
  year = {2026},
  month = jun,
  doi = {10.1097/cm9.0000000000004109},
  url = {https://doi.org/10.1097/cm9.0000000000004109},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Asparagine-linked glycosyltransferase 6 deficiency suppresses tumorigenesis in clear cell renal cell carcinoma by regulating apoptosis and immunotherapy sensitivity
AU  - Zilian Cui
AU  - Ning Wang
AU  - Zonghai Liu
AU  - Shaoan Chen
PY  - 2026
DA  - 2026/06/29
JO  - Chinese Medical Journal
DO  - 10.1097/cm9.0000000000004109
UR  - https://doi.org/10.1097/cm9.0000000000004109
AB  - Background:: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) with a poor prognosis in advanced stages. One of the major challenges in ccRCC treatment is the resistance to tyrosine kinase inhibitors or immune checkpoint inhibitors. Asparagine-linked glycosyltransferase 6 (ALG6) is a glycosyltransferase whose biological role in tumorigenesis remains largely unknown. Therefore, this study aims to investigate its function in ccRCC and its potential involvement in therapeutic resistance.  Methods:: We first analyzed 30 paired ccRCC and adjacent normal tissues from Shandong Provincial Hospital, correlating ALG6 expression with clinicopathological features (age, sex, tumor size, Tumor–Node–Metastasis [TNM] stage). In vitro, CCK-8, colony formation, and apoptosis assays were performed to assess the functional role of ALG6 in ccRCC cell lines. In vivo, a subcutaneous C57BL/6J mouse model and flow cytometry was used to evaluate the effect of ALG6 on the immune microenvironment and anti-PD-1 antibody sensitivity.  Results:: In this study, we found that ALG6 was significantly overexpressed in ccRCC. Elevated ALG6 expression was positively correlated with tumor size and TNM stage, but negatively associated with overall survival in patients with ccRCC. Functional experiments demonstrated that downregulation of endogenous ALG6 markedly suppressed ccRCC cell viability and promoted apoptosis both in vitro and in vivo. Mechanistically, knockdown of ALG6 triggered endoplasmic reticulum (ER) stress, as evidenced by the upregulation of glucose-regulated protein 78 (GRP78) and activation of C/EBP homologous protein (CHOP) in ccRCC cells. Notably, knockdown of ALG6 significantly reduced programmed cell death ligand 1 (PD-L1) expression by inhibiting PD-L1 glycosylation and promoting its ubiquitin-mediated degradation. Furthermore, in vivo experiments demonstrated that ALG6 depletion destabilized PD-L1, enhanced antitumor T-cell immunity, and improved the therapeutic efficacy of anti-PD-1 treatment.  Conclusions:: This study demonstrates that downregulation of ALG6 induces ER stress-mediated apoptosis and enhances antitumor immunity by regulating PD-L1 expression in ccRCC. These findings suggest that ALG6 may serve as a potential therapeutic target for ccRCC.
SN  - 0366-6999
SN  - 2542-5641
ER  -