2. Academic Validation
  3. Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation

Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation

  • Cell Death Differ. 2022 Sep;29(9):1834-1849. doi: 10.1038/s41418-022-00969-2.
Kun Liu  # 1 2,  Liping Jiang  # 1,  Yulin Shi 1 2,  Baiyang Liu 1 2,  Yaomei He 1 2,  Qiushuo Shen 1,  Xiulin Jiang 1 2,  Zhi Nie 1 2 3,  Jun Pu 3,  Cuiping Yang 1 4,  Yongbin Chen 5 6
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
  • 2 Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 3 Kunming Medical University, Kunming, 650500, China.
  • 4 The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China.
  • 5 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China. ybchen@mail.kiz.ac.cn.
  • 6 Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China. ybchen@mail.kiz.ac.cn.
  • # Contributed equally.
PMID: 35301431 DOI: 10.1038/s41418-022-00969-2
Abstract

Gliomas are the most aggressive primary brain tumors. However, no significant improvement in survival has been achieved with the addition of temozolomide (TMZ) or radiation as initial therapy, although many clinical efforts have been carried out to target various signaling pathways or putative driver mutations. Here, we report that Glycosyltransferase 8 domain containing 1 (GLT8D1), induced by HIF-1α under a hypoxic niche, significantly correlates with a higher grade of glioma, and a worse clinical outcome. Depletion of GLT8D1 inhibits self-renewal of glioma stem cell (GSC) in vitro and represses tumor growth in glioma mouse models. GLT8D1 knockdown promotes cell cycle arrest at G2/M phase and cellular Apoptosis with or without TMZ treatment. We reveal that GLT8D1 impedes CD133 degradation through the endosomal-lysosomal pathway by N-linked glycosylation and protein-protein interaction. Directly blocking the GLT8D1/CD133 complex formation by CD133N1~108 (referred to as FECD133), or inhibiting GLT8D1 expression by lercanidipine, suppresses Wnt/β-catenin signaling dependent tumorigenesis both in vitro and in patient-derived xenografts mouse model. Collectively, these findings offer mechanistic insights into how hypoxia promotes GLT8D1/CD133/Wnt/β-catenin signaling during glioma progression, and identify GLT8D1 as a potential therapeutic target in the future.

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