Abstract
BackgroundSimilar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD. In contrast to myoblasts, rhabdomyosarcoma cells do not make the transition from a regulative growth phase to terminal differentiation. Previously we demonstrated that the forced expression of MyoD with its E-protein dimerization partner was sufficient to induce differentiation and suppress multiple growth-promoting genes, suggesting that the dimer was targeting a switch that regulated the transition from growth to differentiation. Our data also suggested that a balance between various inhibitory transcription factors and MyoD activity kept rhabdomyosarcomas trapped in a proliferative state.MethodsPotential myogenic co-factors were tested for their ability to drive differentiation in rhabdomyosarcoma cell culture models, and their relation to MyoD activity determined through molecular biological experiments.ResultsModulation of the transcription factors RUNX1 and ZNF238 can induce differentiation in rhabdomyosarcoma cells and their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. The inhibitory transcription factor MSC also plays a role in controlling miR-206, appearing to function by occluding a binding site for MyoD in the miR-206 promoter.ConclusionsThese findings support a network model composed of coupled regulatory circuits with miR-206 functioning as a switch regulating the transition from one stable state (growth) to another (differentiation).
Highlights
Similar to replicating myoblasts, many rhabdomyosarcoma cells express the myogenic determination gene MyoD
If a central integrating mechanism does exist, multiple pathways should regulate its activity and multiple factors should be able to induce differentiation in RMS. In this manuscript we demonstrate that modulation of multiple different myogenic factors can induce differentiation in rhabdomyosarcoma cells and that their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation
These findings suggest that multiple components of differentiation pathways that converge on miR-206 might be targeted for differentiation therapies in at least some rhabdomyosarcomas
Summary
Many rhabdomyosarcoma cells express the myogenic determination gene MyoD. The demonstration that a forced heterodimer of MyoD and a full-length E-protein suppressed multiple inhibitory mechanisms and induced differentiation in the RD and other rhabdomyosarcomas suggested that a central integrating mechanism might regulate the switch from regulative growth to differentiation [8]. If a central integrating mechanism does exist, multiple pathways should regulate its activity and multiple factors should be able to induce differentiation in RMS In this manuscript we demonstrate that modulation of multiple different myogenic factors can induce differentiation in rhabdomyosarcoma cells and that their activity is integrated, at least in part, through the activation of miR-206, which acts as a genetic switch to transition the cell from a proliferative growth phase to differentiation. These findings suggest that multiple components of differentiation pathways that converge on miR-206 might be targeted for differentiation therapies in at least some rhabdomyosarcomas
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
