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

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.