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Functional loss of a noncanonical BCOR-PRC1.1 complex accelerates SHH-driven medulloblastoma formation.
Genes & Development ( IF 10.5 ) Pub Date : 2020-09-01 , DOI: 10.1101/gad.337584.120
Lena M Kutscher 1, 2 , Konstantin Okonechnikov 1, 2 , Nadja V Batora 1, 2 , Jessica Clark 1, 2 , Patricia B G Silva 1, 2 , Mikaella Vouri 1, 2 , Sjoerd van Rijn 1, 2 , Laura Sieber 1, 2 , Britta Statz 1, 2 , Micah D Gearhart 3 , Ryo Shiraishi 4 , Norman Mack 1, 2 , Brent A Orr 5 , Andrey Korshunov 6, 7 , Brian L Gudenas 8 , Kyle S Smith 8 , Audrey L Mercier 9, 10 , Olivier Ayrault 9, 10 , Mikio Hoshino 4 , Marcel Kool 1, 2, 11 , Katja von Hoff 12 , Norbert Graf 13 , Gudrun Fleischhack 14 , Vivian J Bardwell 3 , Stefan M Pfister 1, 2, 15 , Paul A Northcott 8 , Daisuke Kawauchi 1, 2
Affiliation  

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 (BcorΔE9–10) in GNPs during development. This mutation leads to reduced expression of C-terminally truncated BCOR (BCORΔE9–10). While BcorΔE9–10 alone did not promote tumorigenesis or affect GNP differentiation, BcorΔE9–10 combined with loss of the SHH receptor gene Ptch1 resulted in fully penetrant medulloblastomas. In Ptch1+/−;BcorΔE9–10 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+/−;BcorΔE9–10 tumors. Overall, our data suggests that BCOR–PRC1.1 disruption leads to Igf2 overexpression, which transforms preneoplastic cells to malignant tumors.

中文翻译:

非规范性BCOR-PRC1.1复合物的功能丧失会加速SHH驱动的髓母细胞瘤的形成。

髓母细胞瘤是一种由小脑发育引起的儿童期恶性脑瘤。在声波刺猬(SHH)亚组髓母细胞瘤中,SHH信号的异常激活导致颗粒神经元祖细胞(GNP)增殖增加,并使这些细胞易于发生肿瘤。通常需要第二个合作的基因命中才能将这些增生性细胞推向恶性肿瘤,并赋予与致癌信号相关的突变特异性特征。转录共抑制子BCOR的体细胞功能丧失突变是复发性的,并富含SHH髓母细胞瘤。为了研究BCOR作为候选抑癌,我们使用了基因工程小鼠模型中删除外显子的9/10 BCORBCOR ΔE9-10)。这种突变导致C末端截短的BCOR(BCORΔE9-10)的表达降低。虽然单独使用BcorΔE9-10不会促进肿瘤发生或不影响GNP分化,但是BcorΔE9-10结合SHH受体基因Ptch1的缺失会导致完全穿透的髓母细胞瘤。在PTCH1 +/- ; BCOR ΔE9-10肿瘤,生长因子基因IGF2是异常上调,和异位IGF2过表达足以驱动肿瘤发生中PTCH1 +/-的GNP。BCOR直接调节Igf2,可能是通过PRC1.1复合体;在Ptch1 +/-中Igf2启动子的抑制性组蛋白标记H2AK119Ub降低; BCOR ΔE9-10肿瘤。总体而言,我们的数据表明BCOR–PRC1.1破坏导致Igf2过表达,从而将肿瘤前细胞转化为恶性肿瘤。
更新日期:2020-09-01
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