Loss of suppressor-of-fused function promotes tumorigenesis

Abstract

The Sonic Hedgehog (SHH) signaling pathway is indispensable for development, and functions to activate a transcriptional program modulated by the GLI transcription factors. Here, we report that loss of a regulator of the SHH pathway, Suppressor of Fused (Sufu), resulted in early embryonic lethality in the mouse similar to inactivation of another SHH regulator, Patched1 (Ptch1). In contrast to Ptch1+/- mice, Sufu+/- mice were not tumor prone. However, in conjunction with p53 loss, Sufu+/- animals developed tumors including medulloblastoma and rhabdomyosarcoma. Tumors present in Sufu+/-p53-/- animals resulted from Sufu loss of heterozygosity. Sufu+/-p53-/- medulloblastomas also expressed a signature gene expression profile typical of aberrant SHH signaling, including upregulation of N-myc, Sfrp1, Ptch2 and cyclin D1. Finally, the Smoothened inhibitor, hedgehog antagonist, did not block growth of tumors arising from Sufu inactivation. These data demonstrate that Sufu is essential for development and functions as a tumor suppressor.

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

“…Third, different standards have been used to define Hh signaling activation. Some groups use elevated expression of Gli1 as the read-out of Hhsignaling activation (Stecca et al, 2007;Bhattacharya et al, 2008) whereas others assess expression of several Hh target genes, such as Gli1, PTCH1, sFRP1 and HIP (Thayer et al, 2003;Karhadkar et al, 2004;Ma et al, 2005;Huang et al, 2006;Lee et al, 2007). Similarly, some groups use only immunohistochemistry to detect Hh-signaling activation (Kubo et al, 2004;Liao et al, 2009) whereas most studies use multiple approaches.…”

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

“…Sufu deletion in mice leads to the continuous activation of Hh signal and embryonic lethality at day 9.5 (Cooper et al , 2005; Svard et al , 2006), underscoring the essential role of Sufu for proper 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).…”

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.…”