Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma.
Transcriptional repressor REST drives lineage stage-specific chromatin compaction at Ptch1 and increases AKT activation in a mouse model of medulloblastoma.
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DOI：
10.1126/scisignal.aan8680
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发表时间：
2019-01-22
影响因子：
7.3
通讯作者：
Gopalakrishnan V
中科院分区：
文献类型：
--
作者：
Dobson THW;Tao RH;Swaminathan J;Maegawa S;Shaik S;Bravo-Alegria J;Sharma A;Kennis B;Yang Y;Callegari K;Haltom AR;Taylor P;Kogiso M;Qi L;Khatua S;Goldman S;Lulla RR;Fangusaro J;MacDonald TJ;Li XN;Hawkins C;Rajaram V;Gopalakrishnan V
在髓母细胞瘤（MB）中，RE 1沉默转录因子（REST）的表达和活性在由声刺猬（SHH）通路驱动的肿瘤中增加，特别是SHH-α（3-16岁儿童）和SHH-β（婴儿）亚组。出乎意料的是，与SHH-α肿瘤相比，SHH-β肿瘤显示出更多的神经元成熟，但两者都与患者总体生存率差相关。我们使用一种新的转基因小鼠模型（RESTTG）研究了REST对肿瘤发生的贡献。在该模型中，在谱系定型Patched 1杂合（Ptch 1 +/−）小脑颗粒神经元祖细胞（CGNP）中条件性NeuroD 2控制的REST转基因表达引起显著加速的肿瘤发生和转移及浸润性疾病。机制的研究表明，神经元的成熟背景下特异性的拮抗相互作用之间的转录抑制剂和激活剂，REST和Gli 1，分别。REST升高和Gli 1抑制剂β-Arrestin 1（Arrb 1）的低表达促进增殖细胞中Gli 1活性和Ptch 1表达，尽管Ptch 1启动子处的组蛋白H3 K9甲基化增加。然而，在谱系定型的RESTTG CGNP中，Arrb 1的增加和Gli 1活性的降低以及Ptch 1位点组蛋白H3 K9甲基化的增加导致Ptch 1表达的过早沉默。在人类肿瘤中，与SHH-α肿瘤相比，SHH-β肿瘤中PTCH 1、GLI 1和ARRB 1的表达显著降低。这些发现以及药理学抑制G9 a和组蛋白脱乙酰酶（HDAC）活性后培养物中MB细胞增殖的协同减少支持REST在更多谱系定向细胞中MB进展中的作用。与增殖的祖细胞相比，谱系定型的RESTTG CGNP也表现出磷酸酶张力蛋白同源物（Pten）（Akt激酶的负调节因子）的表达降低。与此一致，人SHH-β肿瘤具有显著较低的PTEN表达，尽管在SHH-α肿瘤中观察到其基因表达的意外降低。药理学阻断AKT促进培养中REST-高细胞的凋亡。我们的研究结果将REST与MB组织和模型中的分化特异性染色质重塑、PTCH 1沉默和AKT过度活化联系起来，揭示了SHH MB患者潜在的亚组特异性治疗靶点。
In medulloblastomas (MBs), the expression and activity of RE1-silencing transcription factor (REST) is increased in tumors driven by the sonic-hedgehog (SHH) pathway, specifically SHH-α (children 3–16 years) and SHH-β (infants) sub-groups. Unexpectedly, SHH-β tumors display more neuronal maturation compared to SHH-α tumors, yet both are correlated with poor overall patient survival. We studied the contribution of REST to tumorigenesis using a novel transgenic mouse model (RESTTG). In this model, conditional NeuroD2-controlled REST transgene expression in lineage committed Patched 1 heterozygous (Ptch1+/−) cerebellar granule neuron progenitors (CGNPs) caused markedly accelerated tumorigenesis and penetrance and infiltrative disease. Mechanistic studies revealed a neuronal maturation context specific antagonistic interplay between the transcriptional repressor and activator, REST and Gli1, respectively. REST elevation and low expression of an inhibitor of Gli1, β-Arrestin1 (Arrb1), promoted Gli1 activity and Ptch1 expression in proliferating cells, in spite of increased histone H3K9 methylation at the Ptch1 promoter. However, in lineage committed RESTTG CGNPs, Arrb1 increase and decreased Gli1 activity in conjunction with increased histone H3K9 methylationat the Ptch1 locus led to premature silencing of Ptch1 expression. In human tumors, PTCH1, GLI1 and ARRB1 expression were significantly decreased in SHH-β tumors compared to SHH-α tumors. These findings as well as the synergistic decrease of MB cell proliferation in culture upon pharmacological inhibition of G9a and histone deacetylase (HDAC) activities support a role for REST in MB progression in more lineage committed cells. Lineage committed RESTTG CGNPs in comparison with proliferating progenitors, also exhibited decreased expression of the phosphatase tensin homolog (Pten), a negative regulator of Akt kinase. Consistent with this, human SHH-β tumors had significantly lower PTEN expression, although an unexpected decrease in its gene expression was seen in SHH-α tumors. Pharmacological blockade of AKT promoted apoptosis in REST-high cells in culture. Our findings linking REST to differentiation-specific chromatin remodeling, PTCH1 silencing, and AKT hyperactivation in MB tissues and models reveal potential subgroup specific therapeutic targets to explore for patients with SHH MB.
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影响因子：
8
作者：
Das, C. M.;Taylor, P.;Gireud, M.;Singh, A.;Lee, D.;Fuller, G.;Ji, L.;Fangusaro, J.;Rajaram, V.;Goldman, S.;Eberhart, C.;Gopalakrishnan, V.
通讯作者：
Gopalakrishnan, V.
影响因子：
1.3
作者：
Gopalakrishnan V
通讯作者：
Gopalakrishnan V
影响因子：
7.5
作者：
Gu B;Lee MG
通讯作者：
Lee MG
影响因子：
64.5
作者：
Ballas, N;Grunseich, C;Mandel, G
通讯作者：
Mandel, G
DOI：
10.1073/pnas.0401827101
发表时间：
2004-07-13
影响因子：
11.1
作者：
Bruce, AW;Donaldson, IJ;Buckley, NJ
通讯作者：
Buckley, NJ