Myogenic regulatory transcription factors regulate growth in rhabdomyosarcoma

Abstract

Rhabdomyosarcoma (RMS) is a pediatric malignacy of muscle with myogenic regulatory transcription factors MYOD and MYF5 being expressed in this disease. Consensus in the field has been that expression of these factors likely reflects the target cell of transformation rather than being required for continued tumor growth. Here, we used a transgenic zebrafish model to show that Myf5 is sufficient to confer tumor-propagating potential to RMS cells and caused tumors to initiate earlier and have higher penetrance. Analysis of human RMS revealed that MYF5 and MYOD are mutually-exclusively expressed and each is required for sustained tumor growth. ChIP-seq and mechanistic studies in human RMS uncovered that MYF5 and MYOD bind common DNA regulatory elements to alter transcription of genes that regulate muscle development and cell cycle progression. Our data support unappreciated and dominant oncogenic roles for MYF5 and MYOD convergence on common transcriptional targets to regulate human RMS growth.DOI: http://dx.doi.org/10.7554/eLife.19214.001

Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding

“…Recent studies have identified a key role for MyoD in driving RMS growth and initiation Tenente et al 2017). During our analysis, we noticed a significant number of MyoD peaks that were gained only in the presence of Twist2 overexpression (Fig.…”

“…Twist2-induced changes in chromatin structure prevent MyoD from accessing its physiologic target genes but also enable MyoD to bind new target genes. Recent studies have suggested that MyoD and Myf5 adopt key roles in regulating RMS growth and initiation (Olguín et al 2011;Tenente et al 2017). Through ChIP-seq of ERMS cell lines, Tenente et al (2017) observed that both factors regulate genes involved in muscle development, growth factor signaling, smooth muscle and endothelial cell biology, and TGF-β signaling.…”

PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability

“…2B and C). Unlike myoblasts, MYF5 is typically missing from RMS, although when present it appears to be mutually exclusive with MYOD1 (21). Another important divergence from normal myogenesis was high expression of the transcriptional amplifier MYCN (Fig.…”

PROX1 transcription factor is a master regulator of myogenic and oncogenic features of rhabdomyosarcoma

“…During myoblast differentiation, PROX1 expression increases and it regulates the expression of other myogenic factors and components of the muscle contractile machinery (Kivela et al, 2016). In experimental RMS models, myogenic regulatory factors are expressed in the tumors regardless of their cells of origin (Tenente et al, 2017). Through chromatin acetylation, PAX3 – FOXO1 fusion gene has been shown to generate active super enhancers to drive MYOD1 and MYCN, which can then drive the expression of MYOG (Gryder et al, 2017).…”

“…During myogenesis, the temporal expression of myogenic regulatory factors MYOD1, MYF5, MYF6, and myogenin drive differentiation and a terminal cell-cycle exit (Buckingham & Rigby, 2014). RMS cells express most of these factors, yet they fail to execute terminal differentiation (Tenente et al, 2017). It has also been suggested that RMS can arise from mesenchymal progenitor cells that reside in several non-muscular tissues (Charytonowicz et al, 2009).…”