Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth
Elevated hexosamine biosynthesis fuels tumor growth by facilitating protein and lipid glycosylation. But which enzyme in this pathway is better to serve as an antitumor target remains unclear. Here, we revealed that targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, exhibits limited inhibitory effects on glioblastoma (GBM), the most lethal brain tumor. This outcome is due to the compensation of NAGK-mediated hexosamine salvage pathway. Unexpectedly, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, down-regulates the expression of other enzymes in this pathway and suppresses SREBP-1, a critical lipogenic transcription factor, effectively inhibiting GBM growth. Unexpectedly, SREBP-1 transcriptionally up-regulates the expression of hexosamine synthesis enzymes, while inhibition of these enzymes in turn down-regulates SREBP-1 activation via reducing N-glycosylation of its transporter, SCAP. Our study identified PGM3 as a promising target for treating GBM. Its inhibition disrupts the SREBP-1 activation-hexosamine synthesis positive feedback regulation to effectively eliminate GBM cells.
Authors
- Yongjun Kou (ORCID: https://orcid.org/0000-0003-1096-3161)
- Liqing He (ORCID: https://orcid.org/0000-0002-0428-814X)
- Chengyao Chiang (ORCID: https://orcid.org/0000-0002-0081-5176)
- Xinmin Yin (ORCID: https://orcid.org/0000-0001-5716-3458)
- Xiaokui Molly Mo (ORCID: https://orcid.org/0000-0002-9797-2687)
- William H. Yong
- Arnab Chakravarti (ORCID: https://orcid.org/0000-0002-5392-8721)
- Yunzhou Fan (ORCID: https://orcid.org/0009-0001-9860-0690)
- Shino Magaki (ORCID: https://orcid.org/0000-0003-0433-5759)
- Étienne Lefai (ORCID: https://orcid.org/0000-0002-3042-7801)
- Timothy F. Cloughesy (ORCID: https://orcid.org/0000-0002-8656-7483)
- Deliang Guo (ORCID: https://orcid.org/0000-0002-8359-390X)
- Xiang Zhang (ORCID: https://orcid.org/0000-0003-1102-6313)
- Yanwei Liu (ORCID: https://orcid.org/0000-0002-4136-3954)
- Feng Geng (ORCID: https://orcid.org/0000-0002-2985-0629)
- Huali Su
- Yubin Zhong (ORCID: https://orcid.org/0009-0008-9973-2944)
- Qiang Wang (ORCID: https://orcid.org/0000-0002-1219-7889)
Institutions
- University of Louisville (US)
- University of California, Los Angeles (US)
- Université Clermont Auvergne (FR)
- University of California, Irvine (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Unité de Nutrition Humaine (FR)
- Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR)
- Centre de Recherche en Nutrition Humaine d'Auvergne (FR)
- The Ohio State University (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-04-18
- DOI
- https://doi.org/10.1126/sciadv.adq0334
- Citations
- 5
- Primary Topic
- Glycosylation and Glycoproteins Research
- Type
- article
- Field-Weighted Citation Impact
- 4.03