GAS41 promotes ITGA4-mediated PI3K/Akt/mTOR signaling pathway and glioma tumorigenesis.

in Biochemical pharmacology by Guanglei Shang, Wenju Zhang, Yanjie Jia, Donglei Ji, Enwei Wei, Chunfeng Gao, Caroline Zeng, Chunyu Wang, Nan Liu, Pengfei Ge, Yunqian Li, Lei Zeng

TLDR

  • The study revealed that GAS41 is a crucial regulator of glioma progression and suggests that targeting GAS41 may be a promising therapeutic strategy for gliomas.
  • The researchers identified GAS41 as a key regulator of the PI3K/Akt/mTOR signaling pathway, promoting cell proliferation and metastasis.
  • GAS41-targeting small molecules were shown to exhibit anti-proliferative activities in glioma cells, providing a potential therapeutic approach.

Abstract

Glioma Amplified Sequence 41 (GAS41) is a chromatin-associated protein that belongs to the YEATS domain family of proteins and is frequently amplified in various tumors. However, its biological function and carcinogenic mechanism in gliomas are not fully understood. In this study, we revealed that GAS41 was upregulated in human glioma tissues and cell lines, and higher expression of GAS41 was significantly associated with poor clinical prognosis. Genetic depletion and chemical inhibition of GAS41 remarkably inhibited glioma cell proliferation and metastasis abilities and induced cellular apoptosis. Furthermore, functional annotation identified that GAS41 was involved in stimulating the expression of membrane protein ITGA4 to activate the downstream PI3K/Akt/mTOR signaling pathway in glioma cell lines. In addition, we synthesized and evaluated a series of small molecules targeting the GAS41 YEATS domain, which yielded effective anti-proliferative activities in glioma cells. Molecular docking revealed that these compounds bound to the GAS41 YEATS domain pocket in a manner similar to Compounds 9 and 3b, providing a structural basis for exploring the selective inhibition of GAS41 as part of an essential molecular framework. Overall, our study illustrates the crucial role of GAS41 in glioma progression and the malignant phenotype and suggests that targeting GAS41 may be a promising therapeutic treatment strategy for gliomas.

Overview

  • The study focused on understanding the biological function and carcinogenic mechanism of Glioma Amplified Sequence 41 (GAS41) in gliomas.
  • The researchers examined the expression of GAS41 in human glioma tissues and cell lines, and investigated its relationship with clinical prognosis.
  • The study aimed to identify the functional pathways and molecules involved in GAS41-mediated glioma progression and to develop potential therapeutic strategies.

Comparative Analysis & Findings

  • GAS41 was upregulated in human glioma tissues and cell lines, and its higher expression was significantly associated with poor clinical prognosis.
  • Genetic depletion and chemical inhibition of GAS41 remarkably inhibited glioma cell proliferation and metastasis abilities and induced cellular apoptosis.
  • The study identified GAS41 as a key regulator of the PI3K/Akt/mTOR signaling pathway in glioma cell lines, promoting the expression of membrane protein ITGA4.

Implications and Future Directions

  • The study's findings suggest that targeting GAS41 may be a promising therapeutic treatment strategy for gliomas, potentially improving patient outcomes.
  • Further research is needed to fully understand the mechanisms of GAS41-mediated glioma progression and to develop effective treatments.
  • The identification of small molecules targeting the GAS41 YEATS domain may provide a structural basis for exploring selective inhibition of GAS41 as part of a molecular framework.
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