MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state.
Rhabdomyosarcomas are characterized by expression of myogenic specification genes, such as MyoD and/or Myf5, and some muscle structural genes in a population of cells that continues to replicate. Because MyoD is sufficient to induce terminal differentiation in a variety of cell types, we have sought to determine the molecular mechanisms that prevent MyoD activity in human embryonal rhabdomyosarcoma cells. In this study, we show that a combination of inhibitory Musculin:E-protein complexes and a novel splice form of E2A compete with MyoD for the generation of active full-length E-protein:MyoD heterodimers. A forced heterodimer between MyoD and the full-length E12 robustly restores differentiation in rhabdomyosarcoma cells and broadly suppresses multiple inhibitory pathways. Our studies indicate that rhabdomyosarcomas represent an arrested progress through a normal transitional state that is regulated by the relative abundance of heterodimers between MyoD and the full-length E2A proteins. The demonstration that multiple inhibitory mechanisms can be suppressed and myogenic differentiation can be induced in the RD rhabdomyosarcomas by increasing the abundance of MyoD:E-protein heterodimers suggests a central integrating function that can be targeted to force differentiation in muscle cancer cells.
Yang
Zhihong
Z
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
MacQuarrie
Kyle L
KL
Analau
Erwin
E
Tyler
Ashlee E
AE
Dilworth
F Jeffery
FJ
Cao
Yi
Y
Diede
Scott J
SJ
Tapscott
Stephen J
SJ
D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D017570:MyoD Protein / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000502:physiology; D055503:Protein Multimerization; D019154:Protein Splicing; D012208:Rhabdomyosarcoma / Q000378:metabolism* / Q000473:pathology
D051792:Basic Helix-Loop-Helix Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C407909:TCF3 protein, human