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Activation of the Hedgehog-Signaling Pathway in Human Cancer and the Clinical Implications

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Activation of the Hedgehog-Signaling Pathway in Human Cancer and the Clinical Implications Oncogene (2010) 29, 469–481 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 $32.00 www.nature.com/onc REVIEW Activation of the hedgehog-signaling pathway in human cancer and the clinical implications L Yang, G Xie, Q Fan and J Xie Wells Center for Pediatric Research, Division of Hematology and Oncology, Department of Pediatrics and IU Simon Cancer Center, Indiana University, Indianapolis, IN, USA The hedgehog pathway, initially discovered by two Nobel found in most basal cell carcinomas (BCCs) and many laureates Drs E Wieschaus and C Nusslein-Volhard in extracutaneous cancers (Xie, 2005; Epstein, 2008; Jiang Drosophila, is a major regulator for cell differentiation, and Hui, 2008; Xie, 2008a, c). The emerging role of Hh tissue polarity and cell proliferation. Studies from many signaling in human cancer further emphasizes the laboratories reveal activation of this pathway in a variety relevance of studying this pathway to human health. of human cancer, including basal cell carcinomas (BCCs), Overall, the general signaling mechanisms of the Hh medulloblastomas, leukemia, gastrointestinal, lung, ovar- pathway is conserved from fly to the humans (Ingham ian, breast and prostate cancers. It is thus believed that and Placzek, 2006). The seven transmembrane domain targeted inhibition of hedgehog signaling may be effective containing protein smoothened (SMO) serves as the key in treatment and prevention of human cancer. Even more player for signal transduction of this pathway, whose exciting is the discovery and synthesis of specific signaling function is inhibited by another transmembrane protein antagonists for the hedgehog pathway, which have Patched (PTC) in the absence of Hh ligands. In the significant clinical implications in novel cancer thera- presence of active Hh ligands, binding of Hh to its peutics. In this review, we will summarize major advances receptor PTC releases this inhibition, allowing SMO to in the last 2 years in our understanding of hedgehog signal downstream, eventually leading to activation of signaling activation in human cancer, interactions between Gli transcription factors. As transcription factors, Gli hedgehog signaling and other pathways in carcinogenesis, molecules can regulate target gene expression by direct potential antagonists for hedgehog signaling inhibition association with a specific consensus sequence located in and their clinical implications for human cancer the promoter region of the target genes (Kinzler and treatment. Vogelstein, 1990; Sasaki et al., 1997). Figure 1 shows a Oncogene (2010) 29, 469–481; doi:10.1038/onc.2009.392; simplified diagram of hedgehog signaling in the presence published online 23 November 2009 or absence of Hh. Keywords: hedgehog; smoothened; cancer; signal transduction; clinical trials and animal model Signal transduction of the hedgehog pathway Hh proteins (one Hh in Drosophila and three Hhs in mammals—Sonic Hedgehog (Shh), Indian Hedgehog Introduction (Ihh) and Desert Hedgehog) are secreted molecules, functioning both on nearby and distant cells in The hedgehog (Hh) gene was identified in 1980 through developing tissues. Following translation, Hh proteins genetic analysis of segmentation of fruit fly Drosophila enter the secretory pathway and undergo autoprocessing (Nusslein-Volhard and Wieschaus, 1980). In the early and lipid modifications that produce a signaling peptide 1990s, three homologs of the Hh gene were identified in modified at its both ends by palmitoyl (N terminus) vertebrates (Echelard et al., 1993; Krauss et al., 1993; and cholesteryl (C terminus) adducts (Lee et al., 1994; Riddle et al., 1993; Chang et al., 1994; Roelink et al., Porter et al., 1995, 1996; Buglino and Resh, 2008). 1994). As an essential developmental signaling pathway, The movement of Hh proteins is regulated by several the Hh pathway is critical for maintaining tissue polarity molecules, such as the transmembrane transporter-like and stem cell population. Inactivation of this pathway protein Dispatched (Disp) (11–14) and metalloproteases causes developmental defects such as holoprosencephaly (Dierker et al., 2009) for release of Hh from secreting (Bale, 2002), whereas hyperactivation of this pathway is cells, the heparan sulfate proteoglycans Dally-like (Dlp) and Dally (Lum et al., 2003; Beckett et al., 2008) or their Correspondence: Professor J Xie, Department of Pediatrics and IU regulators (Baena-Lopez et al., 2008) for extracellular Simon Cancer Center, Indiana University, 980 W. Walnut Street, transport of Hh protein as well as enzymes such as R3-520, Indianapolis, IN 46202, USA. E-mail: [email protected] Sulfateless and Tout velu for heparan sulfate biosynth- Received 23 June 2009; revised 24 September 2009; accepted 30 esis (Bellaiche et al., 1998; Toyoda et al., 2000; Koziel September 2009; published online 23 November 2009 et al., 2004). Hedgehog signaling in human cancer L Yang et al 470 Without Hh With Hh phosphorylation sites are defective in Hh signaling. However, these phosphorylation sites are not conserved in vertebrate SMO, indicative of a different mechanism SMO 3 Gli for SMO signaling in higher organisms (Zhang et al., 2 Gli 2004). There are two important changes during mam- SMO 1 malian SMO signaling. First, SMO protein undergoes PTC Hh conformational changes to favor intermolecular inter- GliR GliA action of SMO (Zhao et al., 2007). It is still not clear how this conformational change is regulated. Second, PTC mammalian SMO protein will be translocated to cilium during Hh signaling. GliR GliA Accumulating evidence from several groups indicate that the primary cilia found on most vertebrate cells Hh target Hh target have an important but undefined role in the Hh pathway Genes Genes (Huangfu et al., 2003; Corbit et al., 2005; Huangfu and PTCH1, Gli1 PTCH1, Gli1 Anderson, 2005; May et al., 2005; Zhang et al., 2005; Hoover et al., 2008). Functions of primary cilium is Figure 1 A simplified model for Hh signaling in Mammalian cells. regulated by large protein complexes involved in SMO is the key signal transducer of the Hh pathway. (a) In the intraflagellar transport (IFT), which functions in retro- absence of the Hh ligands, Hh receptor PTC inhibits SMO signaling via an unknown mechanism. Gli molecules are processed grade and anterograde movement of cargo within the into repressor forms, which turn off the Hh-signaling pathway. (b) primary cilia (Scholey and Anderson, 2006). A number In the presence of Hh, PTC is unable to inhibit SMO. SMO of mutations encoding IFT proteins involved in undergoes conformational changes and is localized to cilium. Gli predominantly primary cilium anterograde IFT have molecules are now processed to active forms (GliA), which will been described, resulting in mice with Hh loss of activate the Hh target genes. function phenotypes (Huangfu et al., 2003; Cortellino et al., 2009). Several Hh components, including SMO Patched (PTC, one PTC in fly and two PTCs in and Gli molecules, are also present at the primary cilium vertebrates- PTCH1 and PTCH2) is the major receptor upon Hh stimulation (Haycraft et al., 2005; Rohatgi for Hh proteins (Stone et al., 1996). Several molecules et al., 2009; Wang et al., 2009; Wilson et al., 2009a). are involved in regulation of Hh reception. Hh- An SMO mutant lacking ciliary translocation blocks interacting protein (HIP) can compete with PTC in Hh Hh signaling (Corbit et al., 2005). Gli3 processing is binding to inhibit Hh signaling (Chuang and McMahon, significantly affected by IFT mutants (Huangfu and 1999). Additional molecules, Ihog (or its vertebrate Anderson, 2005; May et al., 2005; Cortellino et al., homologs CDO and BOC), GAS1 and Glypican-3, are 2009), suggesting that SMO activates downstream also able to bind Hh (Okada et al., 2006; Tenzen et al., molecules at the cilium. Current data indicate that 2006; Yao et al., 2006; Zhang et al., 2006; Allen et al., localization of SMO to cilium is not sufficient to activate 2007; Martinelli and Fan, 2007; Seppala et al., 2007; hedgehog signaling (Rohatgi et al., 2009; Wilson et al., Capurro et al., 2008) although the Hh–Ihog binding 2009a). Using Kif3a tissue-specific gene knockout, mode is very different from Shh–CDO interaction recent studies revealed dual roles of cilium for hedgehog (McLellan et al., 2008). It is still not entirely clear how signaling carcinogenesis in mouse models (Han et al., binding of Hh proteins results in the pathway activation. 2009; Wong et al., 2009). Although Kif3a is required One hypothesis is that the function of SMO is normally for SMO-mediated tumor formation, deletion of Kif3a inhibited by PTC in the absence of Hh. Binding of Hh accelerates Gli2-mediated carcinogenesis. However, it proteins to the receptor PTC shuttles PTC out of cilium is not clear how SMO is transported to the cilium in so that PTC is no longer able to inhibit SMO, leading to response to Hh signaling and how SMO activates SMO signaling to downstream molecules. downstream effectors. One candidate molecule is Very little is known about signaling events immedi- b-arrestin because b-arrestin is shown to regulate ciliary ately downstream of SMO. Although previous studies localization of SMO (Kovacs et al., 2008). The role of did not show direct coupling of SMO to G proteins, cilium for downstream hedgehog signaling is less clear. several recent reports support SMO-G protein coupling Two separate studies indicate that cilium is not required (Riobo et al., 2006; Molnar et al., 2007; Ogden et al., for Su(Fu)-mediated regulation of Gli functions
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