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

Cell Death & Differentiation volume 29, pages 1834–1849 (2022)Cite this article

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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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Fig. 1: Hypoxic induction of GLT8D1 in gliomas.
Fig. 2: GLT8D1 promotes tumor growth.
Fig. 3: GLT8D1 is important for glioma stem cell maintenance.
Fig. 4: GLT8D1 inhibits CD133 protein degradation through the endosomal-lysosomal pathway.
Fig. 5: GLT8D1 promotes Wnt/β-catenin signaling.
Fig. 6: The FECD133 potently inhibits glioma progression.
Fig. 7: Lercanidipine inhibits glioma progression.

Data availability

The data are available to academic researchers from corresponding author upon reasonable request.

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Acknowledgements

We thank Drs. Xiuwu Bian and Yu Shi at Institute of Pathology and Southwest Cancer Centre, The Third Military Medical University, China, for providing us the human primary glioma stem cell lines: GBM1 and GBM2. We thank Dr. Hu Zhou and Jin Gao at Shanghai Institute of Materia Medica, Chinese Academy of Sciences for the Mass spectrometry analysis. We thank Dr. Nigel W. Fraser (Dept of Microbiology, Pereleman School of Medicine, university of Pennsylvania, USA), Dr. Jumin Zhou (Kunming Institute of Zoology, CAS) and Dr. Dangsheng Li (Deputy editor-in-chief of Cell Research) for their instructive comments on the manuscript writing. This study was supported by National Key Research and Development Program of China (2021YFF1000602), National Nature Science Foundation of China (U2102206, U1902216, 82173110, 82160512), Yunnan Applied Basic Research Projects (2019FJ009, 202001AS070037, 2019FB106, 2019FB111 and 2019HB076). C.P.Y was also supported by Youth Innovation Promotion Association, CAS; Yunnan Ten Thousand Talents Plan Young & Elite Talents Project. Y.B.C was supported by grant from the Strategic Priority Research Program of the Chinese Academy of Sciences XDPB17, and YJKYYQ20190048; Science & Technology Department of Sichuan Province Research Program (2020YFSY0009).

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  1. These authors contributed equally: Kun Liu, Liping Jiang.

Authors and 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

    Kun Liu, Liping Jiang, Yulin Shi, Baiyang Liu, Yaomei He, Qiushuo Shen, Xiulin Jiang, Zhi Nie, Cuiping Yang & Yongbin Chen

  2. Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, 100049, China

    Kun Liu, Yulin Shi, Baiyang Liu, Yaomei He, Xiulin Jiang & Zhi Nie

  3. Kunming Medical University, Kunming, 650500, China

    Zhi Nie & Jun Pu

  4. The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China

    Cuiping Yang

  5. Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, Yunnan, 650223, China

    Yongbin Chen

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Contributions

YBC supervised and wrote the manuscript. KL designed and performed the biochemical functional analysis for GLT8D1 in vitro and xenograft tumor models in vivo. LPJ performed the tumor sphere, qRT-PCR, immunoblot, and PDXs analysis, YLS, BYL, YMH, QSS, XLJ, ZN, JP, and CPY performed the bioinformatics analysis, and provided clinical tumor samples.

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Correspondence to Yongbin Chen.

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Mouse care and treatment was approved by the Animal Care and Use Committee at the Kunming Institute of Zoology, Chinese Academy of Sciences. Human resected tissues were obtained from Kunming medical university, China, with informed consent.

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Liu, K., Jiang, L., Shi, Y. et al. Hypoxia-induced GLT8D1 promotes glioma stem cell maintenance by inhibiting CD133 degradation through N-linked glycosylation. Cell Death Differ 29, 1834–1849 (2022). https://doi.org/10.1038/s41418-022-00969-2

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