Targeting PGM3 abolishes SREBP-1 activation-hexosamine synthesis feedback regulation to effectively suppress brain tumor growth.

in Science advances by Huali Su, Yaogang Zhong, Liqing He, Feng Geng, Xinmin Yin, Yongjun Kou, Cheng-Yao Chiang, Xiaokui Mo, Yunzhou Fan, Yanwei Liu, Qiang Wang, Shino Magaki, Timothy F Cloughesy, Etienne Lefai, William H Yong, Arnab Chakravarti, Xiang Zhang, Deliang Guo

TLDR

  • The study reveals that targeting PGM3, an enzyme controlling hexosamine synthesis and salvage pathways, effectively inhibits GBM growth by disrupting the SREBP-1-hexosamine synthesis positive feedback loop.
  • PGM3 is a promising target for treating GBM, and its inhibition could be explored as a therapeutic strategy.
  • The study highlights the importance of understanding the complex interactions between metabolic pathways and their regulation in cancer.

Abstract

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.

Overview

  • The study focuses on the hexosamine biosynthesis pathway and its role in tumor growth, particularly in glioblastoma (GBM).
  • The researchers investigate the potential of targeting different enzymes in this pathway as an antitumor strategy.
  • The primary objective is to identify a suitable target enzyme to achieve effective inhibition of GBM growth.

Comparative Analysis & Findings

  • Targeting GFAT1, the rate-limiting enzyme in hexosamine synthesis, showed limited inhibitory effects on GBM growth due to the compensation of the NAGK-mediated hexosamine salvage pathway.
  • In contrast, inhibiting PGM3, which controls the flux of both de novo hexosamine synthesis and salvage pathways, effectively suppressed GBM growth by down-regulating the expression of other enzymes in this pathway and suppressing the activation of SREBP-1.
  • Inhibition of hexosamine synthesis enzymes also down-regulated SREBP-1 activation by reducing N-glycosylation of the SCAP transporter.

Implications and Future Directions

  • The study suggests that PGM3 is a promising target for treating GBM, as its inhibition disrupts the positive feedback regulation between SREBP-1 and hexosamine synthesis.
  • Future studies should investigate the therapeutic potential of PGM3 inhibition in GBM and explore its combination with other therapies.
  • Elucidating the mechanisms underlying the SREBP-1-hexosamine synthesis axis could provide insights into the development of treatments for other cancers and metabolic disorders.
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