Dottorato in Medicina Molecolare

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Tesi di dottorato

THE DIFFERENTIATION-PROMOTING ACTIVITY OF MIR-206 IN RHABDOMYOSARCOMA  INVOLVES METABOLIC AND EPIGENETIC REPROGRAMMING

Rhadomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. RMS cells resemble fetal myoblasts but are unable to complete the myogenic differentiation program. We have recently shown that miR-206, which is not expressed in RMS, when reintroduced in RMS cells promotes the resumption of differentiation by modulating more than 700 genes. Aiming to define the pathways involved in the myogenic conversion of the tumor cells, we focused our attention on SmyD1 and G6PD, two miR-206 effectors which emerged from our microarray analysis. SmyD1, one of the most upregulated genes, is a H3K4 hystone methylase involved in transcriptional activation. Silencing of SmyD1 did not interfere with the proliferative block imposed by miR-206 but severely impaired miR-206-induced differentiation of RMS cells. Thus it is likely that SmyD1 is necessary in myogenesis to activate a subset of late differentiation genes. Among the genes most highly downregulated by miR-206 we found G6PD, an enzyme involved in the rate-limiting step of the pentose phosphate shunt. We verified that G6PD is indeed a direct target of miR-206. Moreover, we showed that silencing of G6PD in RMS cells has a cytostatic effect, impairing proliferation and soft agar growth. G6PD overexpression did not interfere with the pro-differentiating action of miR-206, suggesting that G6PD downmodulation contributes but is not an absolute requirement for the tumor suppressor potential of miR-206. Altogether these results link miR-206 to epigenetic and metabolic reprogramming, which are presently thought to play a critical role in cancer.

Attività di ricerca

Project: Study of myogenic differentiation and pathogenesis of rhabdomyosarcoma 

Subject area: cellular and molecular biology