Editors' ChoiceCancer

An epigenetic tactic to treat RMS

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Science Signaling  29 Aug 2017:
Vol. 10, Issue 494, eaap7466
DOI: 10.1126/scisignal.aap7466

BET inhibitors may be an effective treatment for some rhabdomyosarcomas.

Alveolar rhabdomyosarcoma (RMS) is an aggressive pediatric cancer in which muscle precursor cells (myoblasts) fail to differentiate and continue to proliferate. A subset of particularly aggressive RMS is driven by a chimeric fusion protein comprising the transcription factors PAX3 (which directs embryonic myogenesis) and FOXO1. Gryder et al. discovered a way to combat the oncogenic effects of the PAX3-FOXO1 fusion. They found that PAX3-FOXO1 recruited the chromatin reader BRD4 to enhancer regions of chromatin near RMS-associated genes. These regions exhibited chromatin remodeling in the form of acetylated and demethylated histone H3K27, generating so-called “super enhancers,” regions of markedly increased gene expression. This was associated with the enhanced production of the PAX3-FOXO1 fusion protein itself, the transcription factors MYOD1 and MYCN, and—through MYOD and MYCN activity—an additional myogenic transcription factor, MYOG. BRD4 was essential for the stability and function of the PAX3-FOXO1 fusion protein. Inhibiting BRD4 with the small molecule JQ1 decreased the abundance of PAX3-FOXO1 protein (but not transcript), the expression of RMS-associated genes, and the growth of RMS tumors in mice. These findings reveal that BET inhibitors may be a therapeutic option for this aggressive type of RMS.

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