Mura, Elena Vittoria (2012) Polycomb protein Ezh2 controls rhabdomyosarcoma formation. Doctoral Thesis.
Rhabdomyosarcoma (RMS) is a sarcoma more frequent in children, which arises from the disruption of regulatory mechanisms that lead to the myogenic phenotype. RMS cells have low levels of muscle differentiation markers. Ezh2 is a histone methyltransferase part of the PRC2 complex and at the early stage of myogenesis it silences muscle specific genes (even MyoD target genes) consenting the proper timing of muscle specific gene expression. During skeletal differentiation in myoblasts, Ezh2 displaces from myogenic regulatory regions and MyoD dependent transcription is co-activated by the complex Cdk9/CycT2. The cyclin dependent kinase 9 and its cyclin partner, the Cyc T2, are MyoD interacting proteins that together form a complex whose main activity is phosphorylating the carboxyl terminal domain of RNApolII on muscle specific promoters allowing stabilization of the nascent transcripts. Surprisingly, its kinase activity is abrogated in RMS. Our results show that Ezh2 depletion in a human rhabdomyosarcoma cell line causes a partial reactivation of the myogenic program, more in particular a reactivation of MyoD target genes such as myosin heavy chain (MyH) and myogenin (Myog) and, in addition these data correlate with an increase in the elongating RnapolII at Myog and Myh promoters. Further analyses demonstrated the restoration of Cdk9 occupancy at Myog and Myh promoters in RD-Ezh2-KD cells providing evidence for an inhibitory effect of EZh2 on Cdk9/CycT2 kinase activity in RMS.
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