Epigenetics in rhabdomyosarcoma: cues to new biomarkers and targeted therapies

In this article of EBioMedicine, Chunxia Liu and colleagues [1] show that guanine nucleotide exchange factor T (GEFT) overexpression in rhabdomyosarcoma (RMS) cell lines and patients’ biopsies is correlated to the methylation status of its promoter region, which is significantly lower in RMS tumours than in normal skeletal muscle, this strictly linking epigenetic aberrations to malignant phenotype. Indeed, epigenetically mediated upregulation of GEFT, a protein involved in Rho-GTPase activation [2], is shown to promote growth, progression and metastasis of RMS cells by controlling specific mediators of the epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) processes, both in vitro and in xenograft mouse models. Specifically, the authors indicate that GEFT functions in RMS tumorigenicity are correlated with the aberrant modulation of the Rac1/Cdc42-PAK1 signalling pathway and its interrelated genes. Altogether, the reported findings are particularly interesting since they provide new insights into the molecular mechanisms involved in the metastatic capacity of RMS cancer cells. In addition to this, they have the translational potential for future personalised therapies, since they propose new possible targets for setting advanced therapeutic strategies against RMS tumours. To better understand the relevance of the scientific data reported by Liu et al., [1] it is essential to underline the importance of epigenetic modifications in cancer progression, mainly in RMS dissemination. RMS is the most frequently diagnosed malignant soft tissue sarcoma in children and adolescents [3]. The two main histological subtypes in childhood are alveolar RMS (ARMS) and embryonal RMS (ERMS), which are characterised by distinct clinicopathological features and outcomes [4]. RMS is particularly aggressive and patients with metastatic or recurrent disease have a poor clinical outcome with a 5-year overall survival of about 30%. Hence, the identification of innovative therapies against advanced RMS represents an urgent clinical need. Tumours commonly share mutations in pivotal genes mainly implicated in cell proliferation and survival, but it is increasingly