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Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.

ABSTRACT: Medulloblastoma is a malignant childhood brain tumor arising from the developing cerebellum. In Sonic Hedgehog (SHH) subgroup medulloblastoma, aberrant activation of SHH signaling causes increased proliferation of granule neuron progenitors (GNPs), and predisposes these cells to tumorigenesis. A second, cooperating genetic hit is often required to push these hyperplastic cells to malignancy and confer mutation-specific characteristics associated with oncogenic signaling. Somatic loss-of-function mutations of the transcriptional corepressor BCOR are recurrent and enriched in SHH medulloblastoma. To investigate BCOR as a putative tumor suppressor, we used a genetically engineered mouse model to delete exons 9/10 of Bcor (Bcor ^ΔE9-10 ) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCOR^ΔE9-10). While Bcor ^ΔE9-10 alone did not promote tumorigenesis or affect GNP differentiation, Bcor ^ΔE9-10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1 ^+/- ;Bcor ^ΔE9-10 tumors, the growth factor gene Igf2 was aberrantly up-regulated, and ectopic Igf2 overexpression was sufficient to drive tumorigenesis in Ptch1 ^+/- GNPs. BCOR directly regulates Igf2, likely through the PRC1.1 complex; the repressive histone mark H2AK119Ub is decreased at the Igf2 promoter in Ptch1 ^+/- ;Bcor ^ΔE9-10 tumors. Overall, our data suggests that BCOR-PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

SUBMITTER: Kutscher LM

PROVIDER: S-EPMC7462063 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Previous studies have evaluated the role of miRNAs in the initiation and progression of cancer. MiR-34a was found to be downregulated in several tumors, including medulloblastoma. We here analysed the function of miR-34a in vivo by targeted transgenesis to generate mice with constitutive deletion of the miR-34a gene, which resulted in the absence of mir-34a in all analysed tissues. Nevertheless, these mice were viable and fertile. A comprehensive standardized phenotypic analysis including more than 300 single parameters performed by the German Mouse Clinic revealed no apparent phenotype. Analysis of miR-34a expression in human medulloblastomas and medulloblastoma cell lines revealed significant downregulation as compared to human cerebellum. Re-expression of mir-34a in human medulloblastoma cells in vitro reduced cell viability, cell proliferation and induced apoptosis. Among the targets downregulated by miR-34a in human medulloblastoma cells were NMYC and SIRT1. Activation of the Shh pathway by targeted overexpression of SmoA1 causes medulloblastoma in mice, which is dependent on the presence and upregulation of NMYC. Analysis of miR-34a in ND2:SmoA1-derived medulloblastomas revealed significant suppression of miR-34a compared to normal cerebellum. Crossbreeding these mice with miR-34a knockout mice significantly accelerated medulloblastoma growth in mice deficient for miR-34a. Interestingly, NMYC and SIRT1 were highly expressed in medulloblastomas derived from these mice. We here demonstrate that miR-34a is dispensable for normal development, but that its loss accelerates medulloblastoma. Strategies aiming to re-express miR-34a in tumors could therefore represent an efficient therapy option. For genome-wide expression analysis total RNA from brain and thymus of three or four male miR34a and four control mice was isolated using RNeasy Midi kit (Qiagen, Hilden, Germany). The cDNA microarrays were generated, hybridized and analysed as described (Horsch et al 2009). Two chip hybridizations were performed with total RNA for each individual mutant mouse against a reference RNA pool of the same organ.

Project description:BCOR is a critical regulator of human development. Heterozygous mutations of BCOR in females cause the X-linked developmental disorder Oculofaciocardiodental syndrome (OFCD), and hemizygous mutations of BCOR in males cause gestational lethality. BCOR associates with Polycomb group proteins to form one subfamily of the diverse Polycomb repressive complex 1 (PRC1) complexes, designated PRC1.1. Currently there is limited understanding of differing developmental roles of the various PRC1 complexes. We therefore generated a conditional exon 9-10 knockout Bcor allele and a transgenic conditional Bcor expression allele and used these to define multiple roles of Bcor, and by implication PRC1.1, in mouse development. Females heterozygous for Bcor exhibiting mosaic expression due to the X-linkage of the gene showed reduced postnatal viability and had OFCD-like defects. By contrast, Bcor hemizygosity in the entire male embryo resulted in embryonic lethality by E9.5. We further dissected the roles of Bcor, focusing on some of the tissues affected in OFCD through use of cell type specific Cre alleles. Mutation of Bcor in neural crest cells caused cleft palate, shortening of the mandible and tympanic bone, ectopic salivary glands and abnormal tongue musculature. We found that defects in the mandibular region, rather than in the palate itself, led to palatal clefting. Mutation of Bcor in hindlimb progenitor cells of the lateral mesoderm resulted in 2/3 syndactyly. Mutation of Bcor in Isl1-expressing lineages that contribute to the heart caused defects including persistent truncus arteriosus, ventricular septal defect and fetal lethality. Mutation of Bcor in extraembryonic lineages resulted in placental defects and midgestation lethality. Ubiquitous over expression of transgenic Bcor isoform A during development resulted in embryonic defects and midgestation lethality. The defects we have found in Bcor mutants provide insights into the etiology of the OFCD syndrome and how BCOR-containing PRC1 complexes function in development.

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Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.

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