HDAC6 and USP9X Control Glutamine Metabolism by Stabilizing GS to Promote Glioblastoma Tumorigenesis.

in Advanced science (Weinheim, Baden-Wurttemberg, Germany) by Go Woon Kim, Minhae Cha, Hien Thi My Ong, Jung Yoo, Yu Hyun Jeon, Sang Wu Lee, Soo Yeon Oh, Min-Jung Kang, Youngsoo Kim, So Hee Kwon

TLDR

  • HDAC6 and USP9X promote GBM tumorigenesis by stabilizing glutamine synthetase, and targeting these enzymes can repress tumorigenesis and disrupt glutamine metabolism.
  • The study identifies HDAC6 and USP9X as potential therapeutic targets for GBM treatment, with potential to combine with existing therapies.

Abstract

Glioblastoma (GBM) is the most common and the deadliest brain cancer. Glutamine anabolism mediated by glutamine synthetase (GS) is beneficial for GBM cell growth, especially under glutamine deprivation. However, the molecular mechanism underlying GS homeostasis in GBM remains undisclosed. Here, it is reported that histone deacetylase 6 (HDAC6) promotes GS deacetylation, stabilizing it via ubiquitin-mediated pathway. It is found that deubiquitination of GS is modulated by ubiquitin-specific peptidase 9, X-linked (USP9X). USP9X stabilizes GS by removing its K48-linked polyubiquitination on lysine 91 and 103. Accordingly, targeting HDAC6 and USP9X in vitro and in vivo represses GBM tumorigenesis by decreasing GS stability. Metabolic analysis shows that silencing HDAC6 and USP9X disrupts de novo nucleotide synthesis, thereby attenuating GBM cell growth. Furthermore, GS modulation by targeting HDAC6 and USP9X restrains the self-renewal capacity. These results suggest that HDAC6 and USP9X are crucial epigenetic enzymes that promote GBM tumorigenesis by modulating glutamine metabolism.

Overview

  • The study focuses on the importance of histone deacetylase 6 (HDAC6) and ubiquitin-specific peptidase 9, X-linked (USP9X) in promoting glutamine synthetase (GS) deacetylation and stability in glioblastoma (GBM) cells.
  • The study aims to understand the molecular mechanism underlying GS homeostasis in GBM and identify potential therapeutic targets for GBM treatment.
  • The study investigates the role of HDAC6 and USP9X in regulating GS stability, with a focus on the impact on glutamine metabolism, cell growth, and self-renewal in GBM cells.

Comparative Analysis & Findings

  • HDAC6 promotes GS deacetylation, stabilizing it via ubiquitin-mediated pathway, whereas USP9X stabilizes GS by removing its K48-linked polyubiquitination on lysine 91 and 103.
  • Targeting HDAC6 and USP9X represses GBM tumorigenesis by decreasing GS stability, disrupts de novo nucleotide synthesis, and attenuates GBM cell growth.
  • GS modulation by targeting HDAC6 and USP9X restrains the self-renewal capacity of GBM cells.

Implications and Future Directions

  • The study highlights the importance of HDAC6 and USP9X as epigenetic enzymes that promote GBM tumorigenesis by modulating glutamine metabolism.
  • Future studies can explore the potential of targeting HDAC6 and USP9X as therapeutic strategies for GBM treatment, potentially combining with existing therapies.
  • The study's findings can also lead to a better understanding of the molecular mechanisms underlying GBM pathogenesis and cancer metabolism, informing the development of novel diagnostic and therapeutic approaches.
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