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DUSP6 regulates radiosensitivity in glioblastoma by modulating the recruitment of phosphorylated DNAPKcs at DNA

Jyothi Nair1,2, Safiulla Basha Syed1, Tejashree Mahaddalkar1,2

  • 1Shilpee Dutt Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India.

Journal of Cell Science
|November 18, 2021
PubMed

Insights

Dual specificity phosphatase 6 (DUSP6) is upregulated in recurrent glioblastoma (GBM). Inhibiting DUSP6 radiosensitizes recurrent GBM cells by affecting DNA repair pathways, offering a potential new treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Glioblastoma (GBM) exhibits poor survival rates due to resistance to chemoradiotherapy, leading to tumor recurrence.
  • Recurrent GBM presents a significant challenge with limited effective treatment options.
  • DUSP6 is implicated as a pro-tumorigenic factor and is known to be upregulated in GBM.

Purpose of the Study:

  • To investigate the role of DUSP6 in recurrent GBM.
  • To explore the therapeutic potential of DUSP6 inhibition in GBM treatment.

Main Methods:

  • Comparative analysis of DUSP6 expression in primary and recurrent GBM patient biopsies.
  • Assessment of DUSP6 localization in GBM cells and patient samples.
  • Evaluation of DUSP6 inhibition effects on GBM cell proliferation, clonogenic survival, and radiosensitivity.
  • Investigation of DUSP6's impact on DNA repair pathway components (DNAPKcs, γH2AX, 53BP1).
  • Testing DUSP6 inhibitors in orthotopic mouse models of GBM.

Main Results:

  • DUSP6 expression is significantly higher in recurrent GBM compared to primary GBM.
  • Nuclear localization of DUSP6 was observed in GBM samples and cell lines.
  • DUSP6 inhibition decreased GBM cell proliferation and clonogenic survival.
  • Inhibition of DUSP6 catalytic activity radiosensitized both primary and recurrent GBM cells.
  • DUSP6 inhibition interfered with the recruitment of phosphorylated DNAPKcs, γH2AX, and 53BP1.
  • DUSP6 inhibition led to decreased cell survival and prolonged growth arrest post-irradiation.
  • DUSP6 inhibition significantly increased progression-free survival in GBM mouse models.

Conclusions:

  • DUSP6 plays a critical role in the progression and radioresistance of recurrent GBM.
  • Nuclear localization of DUSP6 suggests a non-canonical function in DNA repair.
  • DUSP6 inhibition demonstrates therapeutic potential for treating recurrent GBM by enhancing radiosensitivity.
Keywords:
DNAPKcsDUSP6GlioblastomaRadiation resistanceRecurrent GBM

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