JMJD6 promotes transcription pause-release and elongation and glioblastoma cell survival in vivo.

  • Major finding: JMJD6 promotes transcription pause-release and elongation and glioblastoma cell survival in vivo.

  • Concept: An shRNA screen in orthotopic glioblastoma PDXs reveals molecular dependencies not observed in vitro.

  • Impact: Targeting the transcription elongation machinery is a potential therapeutic strategy in glioblastoma.

Therapeutic targeting of chromatin regulators has shown promise in cancer. However, chromatin regulation is often context-specific and may be affected by the tumor microenvironment, limiting the ability of in vitro assays to identify potential targets. Miller and colleagues developed an in vivo shRNA screening strategy to identify regulators of chromatin and transcription required for glioblastoma growth in orthotopic patient-derived xenografts (PDX). Unexpectedly, there was little overlap between the genes required for glioblastoma cell survival in vivo and in vitro, and the in vivo screen uncovered more unique molecular dependencies. Gene expression analysis of cultured glioblastoma cells revealed an enrichment of transcriptional programs associated with proliferation, whereas intracranial tumors were enriched for transcriptional programs associated with stress and signaling responses, including those that rely heavily on transcription pause-release and elongation for expression. Further, the gene expression patterns observed in primary tumors were more similar to the intracranial tumors than the cultured cells. The in vivo screen identified genes involved in transcriptional elongation and pause-release, including the top hit JMJD6, as essential for glioblastoma cell survival in vivo, and JMJD6 was highly expressed in primary gliomas and associated with increased tumor grade. JMJD6 was strongly enriched at enhancers of genes with increased pause-release activity and elevated Pol II binding in vivo, and genes that were transcriptionally paused in vitro were released in vivo. These findings suggest that JMJD6 binding to enhancers increases their activity and promotes pause-release in human glioblastoma cells within the tumor microenvironment. Depletion of JMJD6 had little effect on glioblastoma cell growth in vitro, but suppressed tumor growth and extended survival in glioblastoma PDXs. In addition to suggesting that transcriptional elongation and pause-release may potentially be therapeutically targeted in glioblastoma, these findings indicate that in vivo screening may identify cancer dependencies that are not evident in vitro.

Miller TE, Liau BB, Wallace LC, Morton AR, Xie Q, Dixit D, et al. Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 2017 Jul 5 [Epub ahead of print].