Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Lee, Eunice; Ji, Hongkai; Ouyang, Zhengqing; Zhou, Baiyu; Ma, Wenxiu; Vokes, Steven A.; McMahon, Andrew P.; Wong, Wing H.; Scott, Matthew P.

doi:10.1073/pnas.1004602107

Cited by 113 publications

(111 citation statements)

References 47 publications

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“…Initially, the involvement of Shh signaling in embryonic development of mammal species was discovered. Deprivation of certain molecules of this pathway was found to cause cerebellum atrophy and limb defects in rats (27)(28)(29)(30). Since neoplasms and embryonic development share similar molecular signaling processes, numerous studies have examined and demonstrated the core role of Shh signaling in maintaining tumor growth and cancer cell survival (12).…”

Section: Discussionmentioning

confidence: 99%

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Cheng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. The sonic hedgehog (Shh) pathway has been proven to be involved in embryonic development and cancer growth. GDC-0449, an antagonist of the hedgehog signaling receptor Smoothened (Smo), was recently approved by the US Food and Drug Administration as a prescription for skin basal cell carcinoma. However, the efficacy of GDC-0449 in the treatment of colon cancer and other malignancies, such as basal cell carcinoma and pancreatic cancer, has remained to be proven. The present study assessed the effect of GDC-0449 on the colon cancer cell lines Caco-2 and Ht-29. A Cell Counting Kit-8 assay was applied to assess the cell proliferation rate and apoptosis was tested by flow cytometry. Reverse-transcription quantitative PCR and western blot analysis were used for analyzing expression levels of target genes. Cell proliferation was inhibited, while apoptosis was increased by GDC-0449, whereas the expression of B-cell lymphoma 2 (Bcl-2), a downstream target of Shh signaling, was decreased. Consistent with the inhibition of Gli1 expression, the cancer stem cell markers CD44 and ALDH were decreased in the presence of GDC-0449. In conclusion, GDC-0449 was shown to inhibit the replication of colon cancer cells and trigger apoptosis through downregulating Bcl-2. This may also influence the stemness of cancer stem cells as indicated by the decreased stem cell surface markers.

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Section: Discussionmentioning

confidence: 99%

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Cheng

et al. 2017

Experimental and Therapeutic Medicine

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“…These cells were differentiated for a total of 4 days with addition of the HH stimulant purmorphamine for the final 2 days. NANOG binding was assessed at enhancers for Gli1 and Ptch1 that are bound by multiple GLI proteins in a range of different tissues (9,10,52). Upon HH activation, there was a significant increase in NANOG binding to both enhancers (Fig.…”

Section: Discussionmentioning

confidence: 99%

The Pluripotency Factor NANOG Binds to GLI Proteins and Represses Hedgehog-mediated Transcription

Lex

Chung

et al. 2016

Journal of Biological Chemistry

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The Hedgehog (HH) signaling pathway is essential for the maintenance and response of several types of stem cells. To study the transcriptional response of stem cells to HH signaling, we searched for proteins binding to GLI proteins, the transcriptional effectors of the HH pathway in mouse embryonic stem (ES) cells. We found that both GLI3 and GLI1 bind to the pluripotency factor NANOG. The ectopic expression of NANOG inhibits GLI1-mediated transcriptional responses in a dose-dependent fashion. In differentiating ES cells, the presence of NANOG reduces the transcriptional response of cells to HH. Finally, we found that Gli1 and Nanog are co-expressed in ES cells at high levels. We propose that NANOG acts as a negative feedback component that provides stem cell-specific regulation of the HH pathway.The HH 3 pathway is essential for regulating biological processes in a diverse set of cells. HH ligands, including Sonic hedgehog, bind to the Patched1 (PTCH1) receptor, which activates the transmembrane protein Smoothened, resulting in pathway activation (for a review, see Ref. 1). The transcriptional response to HH ligands is mediated by the GLI family of transcription factors (GLI1-3), which can act as both transcriptional activators and repressors in a context-dependent fashion (for a review, see Ref. 2). The presence of HH ligand causes the maturation of full-length GLI proteins into their transcriptional activator forms (GLI-A), whereas in the absence of ligand GLI proteins undergo C-terminal truncation and then act as transcriptional repressors (GLI-R). Although GLI2 and GLI3 exist in both activator and repressor forms, GLI2 is the major activator, whereas GLI3 is the major repressor (3-5). In contrast, GLI1 only exists as a full-length activator form (5-7). Gli1 is a direct HH target gene, thereby participating in a positive feedback loop (8 -11).The HH pathway was initially characterized for its role in regulating embryonic development, but it also has critical roles in regulating the homeostasis of several adult tissues (for a review, see Ref. 12). In particular, HH regulates two major neural stem cell populations in the brain, the ventral subventricular zone and subgerminal zone, as well as quiescent hair follicle stem cells (13). In the absence or inhibition of the HH pathway, these tissues undergo a marked reduction in the number of proliferating cells, indicating that the pathway is required for normal proliferation (14). Conversely, hyperactivation of the HH pathway results in an expanded population of neural stem cells. In this context, the progeny of neural stem cells is shifted so that they preferentially give rise to two daughter stem cells instead of producing transient amplifying cells capable of generating differentiated progeny (15). Together these results indicate that the levels of HH perceived by neural stem cells regulate the balance between generating stem cells and differentiated progenitors. In addition to regulating normal neural development, various studies have suggested that populations...

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“…To examine whether Brg binds to the Gli regulatory regions of Shh target genes, we compared published genomewide Brg chromatin immunoprecipitation (ChIP)-seq data (28) with ChIP-chip data for Gli1 and Gli3 (29)(30)(31). We observed a high frequency of overlapping binding sites around Shh target genes [global analysis and two examples (Ptch1 and Gli1) are shown in Fig.…”

Section: Brg Binds To Shh Target Gene Regulatory Regions In a Gli-depmentioning

confidence: 99%

Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development

Zhan

Shi

Zhang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

117

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Sonic hedgehog (Shh) signaling plays diverse roles during animal development and adult tissue homeostasis through differential regulation of Gli family transcription factors. Dysregulated Shh signaling activities have been linked to birth defects and tumorigenesis. Here we report that Brg, an ATP-dependent chromatin remodeling factor, has dual functions in regulating Shh target gene expression. Using a Brg conditional deletion in Shh-responding neural progenitors and fibroblasts, we demonstrate that Brg is required both for repression of the basal expression and for the activation of signal-induced transcription of Shh target genes. In developing telencephalons deficient for Brg, Shh target genes were derepressed, whereas Brg-deleted cerebellar granule neuron precursors failed to respond to Shh to increase their proliferation. The repressor function of Brg was mediated through Gli3 and both the repressor and activator functions of Brg appeared to be independent of its ATPase activity. Furthermore, Brg facilitates Gli coactivator histone deacetylase (HDAC) binding to the regulatory regions of Shh target genes, providing a possible mechanism for its positive role in Shh signaling. Our results thus reveal that a complex chromatin regulation mechanism underlies the precise transcription outcomes of Shh signaling and its diverse roles during development.Gli proteins | neural development | SWI/SNF complexes | transcription regulation | signal transduction

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Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Cited by 113 publications

References 47 publications

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

Smoothened antagonist GDC-0449 (Vismodegib) inhibits proliferation and triggers apoptosis in colon cancer cell lines

The Pluripotency Factor NANOG Binds to GLI Proteins and Represses Hedgehog-mediated Transcription

Dual role of Brg chromatin remodeling factor in Sonic hedgehog signaling during neural development

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