2. Academic Validation
  3. An EGFR co-amplified lncRNA HELDR promotes glioblastoma malignancy through KAT7-driven gene programs

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

  • Nat Cell Biol. 2026 May;28(5):972-985. doi: 10.1038/s41556-026-01924-w.
Xiaozhou Yu 1,  Xiao Song 1,  Richard A Schäfer 2,  Qingshu Meng 2,  Deanna Tiek 1 3,  Runxin Wu 1,  Qiu He 1,  Maya Walker 1,  Qi Cao 2,  Rendong Yang 2,  Bo Hu 4,  Shi-Yuan Cheng 5
Affiliations

Affiliations

  • 1 The 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.
  • 2 Department of Urology, Northwestern University Feinberg School of Medicine, Department of Urology & Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 3 Center for Immunotherapy & Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA.
  • 4 The 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. [email protected].
  • 5 The 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. [email protected].
PMID: 41896311 DOI: 10.1038/s41556-026-01924-w
Abstract

EGFR amplification frequently occurs within extrachromosomal DNAs (ecDNAs) and is the most prevalent mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we show a long non-coding RNA (lncRNA) that is co-amplified with EGFR, which we name hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-selective lncRNA that promotes tumorigenicity independent of EGFR signalling. HELDR exhibits widespread chromatin association and recruits the transcription co-activator p300 to the KAT7 promoter. p300-induced H3K27ac at the KAT7 promoter enlists Other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac and H4K12ac that activate KAT7-driven gene programmes that are critical for GBM malignancy. Targeting KAT7 or HELDR markedly enhances therapeutic effects of anti-EGFR treatments for GBM. These results not only reveal the role of HELDR in EGFR-amplified GBM but also provide a strong rationale to characterize the role of lncRNAs co-amplified with driver oncogenes in human cancers.

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