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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

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Nuclear GSK3β promotes tumorigenesis by phosphorylating KDM1A and inducing its deubiquitylation by USP22

Aidong Zhou1, Kangyu Lin1, Sicong Zhang1,2

  • 1Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Nature Cell Biology
|August 9, 2016
PubMed

Insights

Glycogen synthase kinase 3 beta (GSK3β) promotes glioblastoma by stabilizing KDM1A, a histone demethylase. Inhibiting GSK3β with tideglusib reduces KDM1A, sensitizing tumors and improving survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Glycogen synthase kinase 3 beta (GSK3β) is implicated in various cancers, but its precise role in glioblastoma tumorigenesis is unclear.
  • Understanding the molecular mechanisms of GSK3β in cancer is crucial for developing targeted therapies.

Purpose of the Study:

  • To elucidate the role of nuclear GSK3β in glioblastoma.
  • To identify the downstream targets and mechanisms regulated by GSK3β in cancer stem cell self-renewal and tumor formation.

Main Methods:

  • Investigated the interaction between GSK3β, KDM1A, and USP22.
  • Analyzed histone H3K4 methylation patterns and gene expression (BMP2, CDKN1A, GATA6).
  • Utilized a GSK3 inhibitor (tideglusib) in mouse glioblastoma xenograft models.

Main Results:

  • Nuclear GSK3β phosphorylates KDM1A, promoting its stabilization via USP22-mediated deubiquitylation.
  • Stabilized KDM1A reduces histone H3K4 methylation, repressing tumor-suppressor gene transcription.
  • KDM1A levels correlate with nuclear GSK3β and USP22 in human glioblastoma.
  • Tideglusib treatment downregulates KDM1A, enhances chemotherapy efficacy, and improves survival in mice.

Conclusions:

  • Nuclear GSK3β and USP22 stabilize KDM1A, driving glioblastoma stem cell self-renewal and tumorigenesis.
  • Targeting GSK3β with inhibitors like tideglusib represents a potential therapeutic strategy for glioblastoma.

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