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A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide

Nan Sun1, Qun Chen2, Hao Chen3,1

  • 1Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.

Neuro-Oncology
|December 14, 2024
PubMed
Abstract

Insights

A novel noncoding RNA, HSD52, drives temozolomide (TMZ) resistance in glioblastoma (GBM) by stabilizing NONO/SFPQ interactions. Targeting HSD52 offers a promising strategy to enhance TMZ chemotherapy efficacy in GBM patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Glioblastoma (GBM) treatment faces a major hurdle due to emerging temozolomide (TMZ) resistance.
  • Non-POU domain-containing octamer-binding protein (NONO) and splicing factor proline/glutamine rich (SFPQ) are key nuclear proteins involved in genome stability and gene regulation.
  • The specific role of NONO and SFPQ in GBM's TMZ resistance remains largely unexplored.

Purpose of the Study:

  • To investigate the role of NONO and SFPQ in TMZ resistance in glioblastoma.
  • To identify novel molecular targets for overcoming TMZ resistance in GBM.
  • To explore the therapeutic potential of targeting identified mechanisms to improve GBM treatment outcomes.

Main Methods:

  • RNA-binding protein immunoprecipitation-microarray and RNA microarray were utilized to identify HSD52 in TMZ-resistant and parental GBM cells.
  • In vitro assays, intracranial xenograft, and GBM organoid models were employed to assess HSD52's impact on TMZ resistance.
  • Mechanisms were elucidated using DNA methylation chip, RNA immunoprecipitation, and RNA pull-down assays, with analysis of GBM clinical samples.

Main Results:

  • A novel noncoding RNA, HSD52, was identified and found to be highly expressed in TMZ-resistant GBM, facilitating NONO and SFPQ interaction.
  • HSD52 transcription is upregulated via DNA hypomethylation through H3 ubiquitination attenuation and reduced DNMT1 recruitment.
  • HSD52 promotes NONO/SFPQ complex binding to UFL1 mRNA, enhancing its stability and activating the ATM signaling pathway, ultimately conferring TMZ resistance.

Conclusions:

  • HSD52 plays a critical role in promoting malignant progression and TMZ resistance in glioblastoma.
  • HSD52 facilitates TMZ resistance by stabilizing the NONO/SFPQ complex and activating the ATM signaling pathway.
  • HSD52 represents a promising therapeutic target for overcoming TMZ resistance and improving the clinical efficacy of TMZ chemotherapy in GBM.
Keywords:
DNA damage repair | glioblastoma | HSD52NONO/SFPQ complextemozolomide resistance

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