An EGFR Co-amplified Long Noncoding RNA HELDR Promotes Glioblastoma Malignancy through KAT7-driven gene programs [HELDR]

EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.