RNA-seq Profiles in Transcription elongation factors are in vivo-specific cancer dependencies in glioma

Glioblastoma ranks as one of the most lethal human cancers, with no effective therapies. To discover novel therapeutic targets, here we performed parallel in vivo and in vitro RNA interference screens of epigenetic regulators and show that transcription elongation factors are essential for human glioblastoma cell survival in vivo, but not in vitro. Context-specific dependency in vivo is driven by microenvironment-induced global changes in the cancer epigenome. JMJD6, a top in vivo-specific hit, binds at enhancers and correlates with increased transcription of known pause-controlled genes. JMJD6 knockdown in patient-derived glioblastoma cells enhances survival of mice bearing orthotopic tumors. Moreover, elevated levels of JMJD6 alone, as well as transcription elongation factors collectively, informs tumor grade and predicts poor prognosis for patients. Our work provides a rationale for targeting transcription elongation as a therapeutic strategy in glioblastoma and, more broadly, the power of in vivo phenotypic screening to identify therapeutically relevant targets in cancer. Overall design: RNA-seq of primary patient-derived GBM cells grown in in vivo tumor microenvironment or in vitro in serum free cell culture

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Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, Factor DC, Kim LJY, Morrow JJ, Wu Q, Mack SC, Hubert CG, Gillespie SM, Flavahan WA, Hoffmann T, Thummalapalli R, Hemann MT, Paddison PJ, Horbinski CM, Zuber J, Scacheri PC, Bernstein BE, Tesar PJ, Rich JN