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Updated: Mar 29, 2026

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An EGFR co-amplified lncRNA HELDR promotes glioblastoma malignancy through KAT7-driven gene programs

Xiaozhou Yu1, Xiao Song1, Richard A Schäfer2

  • 1The Ken & Ruth Davee Department of Neurology, The Lou and Jean Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Simpson Querrey Institute for Epigenetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Nature Cell Biology
|March 28, 2026
PubMed

Insights

A novel long non-coding RNA, HELDR, drives glioblastoma (GBM) growth independently of EGFR. Targeting HELDR or KAT7 enhances anti-EGFR therapies for GBM, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Epidermal growth factor receptor (EGFR) amplification is common in glioblastoma (GBM) but targeting it has yielded limited success.
  • Extrachromosomal DNAs (ecDNAs) frequently harbor EGFR amplification in GBM.
  • The role of co-amplified non-coding RNAs in GBM tumorigenesis is not well understood.

Purpose of the Study:

  • To identify and characterize novel non-coding RNAs co-amplified with EGFR in GBM.
  • To elucidate the functional role of the identified long non-coding RNA (lncRNA) in GBM development and progression.
  • To explore therapeutic strategies targeting this lncRNA and its downstream effectors in GBM.

Main Methods:

  • Identification of a novel lncRNA, hidden EGFR long non-coding downstream RNA (HELDR), co-amplified with EGFR.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to assess chromatin association and histone modifications.
  • Molecular assays to investigate the recruitment of p300 and its effect on KAT7 transcription.
  • Assessment of KAT7-driven gene expression and its impact on GBM malignancy.
  • In vivo studies to evaluate the therapeutic efficacy of targeting HELDR or KAT7 in combination with anti-EGFR treatments.

Main Results:

  • HELDR is a GBM-selective lncRNA that promotes tumorigenicity independently of EGFR signaling.
  • HELDR recruits p300 to the KAT7 promoter, leading to increased H3K27ac and subsequent activation of KAT7 transcription.
  • KAT7 activation results in H3K14ac and H4K12ac, driving gene programs critical for GBM malignancy.
  • Targeting HELDR or KAT7 significantly enhances the therapeutic effects of anti-EGFR treatments in GBM models.

Conclusions:

  • HELDR plays a crucial role in EGFR-amplified GBM by activating KAT7 and promoting malignancy.
  • Targeting HELDR or KAT7 represents a promising therapeutic strategy to overcome resistance to anti-EGFR therapies in GBM.
  • This study highlights the importance of investigating lncRNAs co-amplified with driver oncogenes in cancer.

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