An EGFR Co-Amplified and De Novo Long Noncoding RNA HELDR Promotes Glioblastoma Malignancy through KAT7-Driven Gene Programs

EGFR amplification frequently happens within extrachromosome DNAs (ecDNAs) and is a major mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments has been unsuccessful. Here we characterized a long non-coding RNA (lncRNA) that is co-amplified with EGFR within ecDNAs that we name hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR signaling. HELDR globally binds genomic DNA 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 programs 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-driven GBM but also provide a strong rationale to characterize the role of lncRNAs co-amplified with driver oncogenes in human cancers.