Mutations in SUFU predispose to medulloblastoma

Abstract

The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.

The EWS/FLI1 oncogenic transcription factor deregulates GLI1

“…The phenotype of these mice has features resembling Gorlin's syndrome, the cancerpredisposing condition resulting from PATCHED1 insufficiency in humans. SUFU mutation has been found to be associated with some cases of human medulloblastoma (Taylor et al, 2002), but these cases are rare (Koch et al, 2004). These findings serve as a precedent for deregulation of GLI1 in the absence of aberrancy of HH or PATCHED.…”

SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development

“…Importantly, heterozygous loss of Sufu, in conjunction with the loss of p53, leads to the development of medulloblastoma and rhabdomyosarcoma (Lee et al , 2007). Germline Sufu mutations have been identified in medulloblastoma (Taylor et al , 2002; Kool et al , 2014) and associated with the development of medulloblastoma in Gorlin syndrome (Pastorino et al , 2009; Kijima et al , 2012; Smith et al , 2014). Furthermore, somatic Sufu mutations have been identified in multiple other malignancies, including prostate cancer (Sheng et al , 2004).…”

Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin–proteasome pathway

“…These biochemical activities of Sufu are conserved in mammals (Kogerman et al, 1999;Jacob and Lum, 2007), and mammalian Sufu was also found to possess a nuclear activity in repressing Gli-mediated transcription via its interaction with SAP18 (Cheng and Bishop, 2002), a component of the Sin3-HDAC corepressor complex. Sufu mutations are present in 9% of medulloblastoma patients (Taylor et al, 2002), and mice that carry one target-inactivated Sufu allele exhibited heightened risk of developing medulloblastoma in p53 null background (Lee et al, 2007). Although Drosophila Sufu is not essential for embryonic development, mouse embryos devoid of Sufu die early because of multiple developmental anomalies including failure to close the neural tube (Cooper et al, 2005;Svard et al, 2006), a phenotype shared by inactivation of Ptch1.…”