Nos2 Inactivation Promotes the Development of Medulloblastoma in Ptch1+/− Mice by Deregulation of Gap43–Dependent Granule Cell Precursor Migration

Haag, Daniel; Zipper, Petra; Westrich, Viola; Karra, Daniela; Pfleger, K.; Toedt, Grischa; Blond, Fréderic; Delhomme, Nicolas; Hahn, Meinhard; Reifenberger, Julia; Reifenberger, Guido; Lichter, Peter

doi:10.1371/journal.pgen.1002572

Cited by 26 publications

(22 citation statements)

References 74 publications

(87 reference statements)

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“…On the contrary, compromised cell migration may also make cells more susceptible to transformation. The latter is best illustrated by medulloblastoma tumorigenesis in which granule neuronal precursors fail to migrate to their destination over time and therefore acquire additional time for mitosis and are more likely to be transformed [37-39]. Our previous experiments identified a group of KMT2D-regulated genes that are functionally linked to cell migration and extracellular matrices [35].…”

Section: Resultsmentioning

confidence: 99%

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation

Guo

Chen²,

Huang³

et al. 2013

Oncotarget

113

103

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KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

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Section: Resultsmentioning

confidence: 99%

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation

Guo

Chen²,

Huang³

et al. 2013

Oncotarget

113

103

View full text Add to dashboard Cite

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“…Examples of numerous tissue-restricted genes regulated by Hh signaling include Vascular Endothelial Growth Factors (VEGF), Angiopoietin-1 and Angiopoietin-2 in endothelial cells 31, 32 . Snail, Zeb1,2, Twist2, FoxF1 in fibroblasts 33-35 -smooth muscle actin, vimentin and IL-6 in myofibroblasts 36, 37 , N-myc in neurons regulating development and myelination 38, 39 , BMI, Sox2, Nanog in cancer stem cells 7, 40 (Table 1). …”

Section: Overview Of the Hh Signaling Pathway In Mammalian Cellsmentioning

confidence: 99%

Inhibition of Hedgehog signaling in the gastrointestinal tract: Targeting the cancer microenvironment

Merchant

Saqui‐Salces

2014

Cancer Treatment Reviews

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This review summarizes emerging information regarding the Hedgehog (Hh) signaling pathway during neoplastic transformation in the gastrointestinal tract. Although there is a role for the well-established canonical pathway in which Hedgehog ligands interact with their receptor Patched, there is sufficient evidence that downstream components of the Hh pathway, e.g., Gli1, are hijacked by non-Hh signaling pathways to promote the conversion of the epithelium to dysplasia and carcinoma. We review the canonical pathway and involvement of primary cilia, and then focus on current evidence for Hh signaling in luminal bowel cancers as well as accessory organs, i.e., liver, pancreas and biliary ducts. We conclude that targeting the Hh pathway with small molecules, nutriceuticals and other mechanisms will likely require a combination of inhibitors that target Gli transcription factors in addition to canonical modulators such as Smoothened.

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“…In physiological conditions, the GCPs intensely proliferate postnatally in the EGL mitogenic niche, under the stimulus of Shh, and exit the cell cycle and differentiate as a result of migrating inward to molecular and internal granular layers (ML and IGL, respectively) (Choi et al, 2005). Given that the prolonged mitotic activity makes the GCPs especially susceptible to cell transformation (Wang and Zoghbi, 2001), the rate of migration, by regulating the duration of the period during which GCPs remain proliferating in the EGL, can impact the incidence of MBs, as we and others have shown (Farioli-Vecchioli et al, 2012, 2013; Haag et al, 2012). In fact, our recent study demonstrated that a new MB Shh-type mouse model, which lacks the MB-suppressor gene Tis21 ( Ptch1 +/- / Tis21 -/- ), develops MBs with high frequency in consequence of a defect of migration of the GCPs out of the EGL (Farioli-Vecchioli et al, 2007, 2012).…”

Section: Introductionmentioning

confidence: 97%

Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

2016

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Medulloblastoma (MB), tumor of the cerebellum, remains a leading cause of cancer-related mortality in childhood. We previously showed, in a mouse model of spontaneous MB (Ptch1+/-/Tis21-/-), that a defect of the migration of cerebellar granule neuron precursor cells (GCPs) correlates with an increased frequency of MB. This occurs because GCPs, rather than migrating internally and differentiating, remain longer in the proliferative area at the cerebellar surface, becoming targets of transforming insults. Furthermore, we identified the chemokine Cxcl3 as responsible for the inward migration of GCPs. As it is known that preneoplastic GCPs (pGCPs) can still migrate and differentiate like normal GCPs, thus exiting the neoplastic program, in this study we tested the hypothesis that pGCPs within a MB lesion could be induced by Cxcl3 to migrate and differentiate. We observed that the administration of Cxcl3 for 28 days within the cerebellum of 1-month-old Ptch1+/-/Tis21-/- mice, i.e., when MB lesions are already formed, leads to complete disappearance of the lesions. However, a shorter treatment with Cxcl3 (2 weeks) was ineffective, suggesting that the suppression of MB lesions is dependent on the duration of Cxcl3 application. We verified that the treatment with Cxcl3 causes a massive migration of pGCPs from the lesion to the internal granular layer, where they differentiate. Thus, the induction of migration of pGCPs in MB lesions may open new ways to treat MB that exploit the plasticity of the pGCPs, forcing their differentiation. It remains to be tested whether this plasticity continues at advanced stages of MB. If so, these findings would set a potential use of the chemokine Cxcl3 as therapeutic agent against MB development in human preclinical studies.

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Nos2 Inactivation Promotes the Development of Medulloblastoma in Ptch1+/− Mice by Deregulation of Gap43–Dependent Granule Cell Precursor Migration

Cited by 26 publications

References 74 publications

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation

Inhibition of Hedgehog signaling in the gastrointestinal tract: Targeting the cancer microenvironment

Suppression of Medulloblastoma Lesions by Forced Migration of Preneoplastic Precursor Cells with Intracerebellar Administration of the Chemokine Cxcl3

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