Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation.
Disease-associated KBTBD4 mutations in medulloblastoma elicit neomorphic ubiquitylation activity to promote CoREST degradation.
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DOI：
10.1038/s41418-022-00983-4
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发表时间：
2022-10
影响因子：
12.4
通讯作者：
D'Angiolella, Vincenzo
中科院分区：
文献类型：
--
作者：
Chen, Zhuoyao;Ioris, Rafael M.;Richardson, Stacey;Van Ess, Ava N.;Vendrell, Iolanda;Kessler, Benedikt M.;Buffa, Francesca M.;Busino, Luca;Clifford, Steven C.;Bullock, Alex N.;D'Angiolella, Vincenzo
髓母细胞瘤是儿童最常见的恶性脑肿瘤。基因组研究已经确定了不同的疾病亚组：wnt/无翼（WNT），音刺猬（SHH），和非WNT/非SHH，包括组3和组4。WNT和SHH信号的改变形成了它们亚组的发病基础，而非WNT/非SHH肿瘤的发病基础在很大程度上仍然是难以捉摸的。最近的分析显示，在3/4组髓母细胞瘤的病例中，E3泛素连接酶接头Kelch重复序列和BTB结构域包含4（KBTBD4）中经常出现框内插入。重要的是，具有KBTBD4突变的第3/4组肿瘤通常缺乏其他基因特异性改变，例如MYC扩增，表明KBTBD4插入突变是主要的遗传驱动因素。因此，描述KBTBD4突变的作用为了解肿瘤发病机制和利用基础机制进行治疗提供了重要机会。在这里，我们展示了癌症发病机制中的一种新机制，即KBTBD4中的indel突变驱动其识别新底物进行降解。我们观察到KBTBD4突变体促进REST辅阻遏物（CoREST）的募集和泛素化，其形成复合物以调节染色质可及性和转录程序。由KBTBD4突变促进的CoREST的降解转移表观遗传程序，诱导转录的显著改变以促进癌细胞的干细胞性增加。通过RNA-seq对> 200例人类第3组和第4组髓母细胞瘤进行的转录分析突出了具有KBTBD4突变的肿瘤中存在CoREST和干细胞样特征，其延伸到非突变肿瘤的进一步子集，表明CoREST改变是第3组和第4组中广泛相关的新发病机制。我们的研究结果揭示了KBTBD4突变作为非WNT/非SHH髓母细胞瘤中表观遗传重编程的新驱动因素，通过泛素连接酶中的功能获得性突变（新底物募集）建立了一种新的肿瘤发生模式，并将突变的KBTBD4和CoREST复合物鉴定为改进肿瘤特异性治疗的新药物靶点。
Medulloblastoma is the most common malignant brain tumour in children. Genomic studies have identified distinct disease subgroups: wnt/wingless (WNT), sonic hedgehog (SHH), and non-WNT/non-SHH, comprising group 3 and group 4. Alterations in WNT and SHH signalling form the pathogenetic basis for their subgroups, whereas those for non-WNT/non-SHH tumours remain largely elusive. Recent analyses have revealed recurrent in-frame insertions in the E3 ubiquitin ligase adaptor Kelch Repeat and BTB Domain Containing 4 (KBTBD4) in cases of group 3/4 medulloblastoma. Critically, group 3/4 tumours with KBTBD4 mutations typically lack other gene-specific alterations, such as MYC amplification, indicating KBTBD4 insertion mutations as the primary genetic driver. Delineating the role of KBTBD4 mutations thus offers significant opportunities to understand tumour pathogenesis and to exploit the underpinning mechanisms therapeutically. Here, we show a novel mechanism in cancer pathogenesis whereby indel mutations in KBTBD4 drive its recognition of neo-substrates for degradation. We observe that KBTBD4 mutants promote the recruitment and ubiquitylation of the REST Corepressor (CoREST), which forms a complex to modulate chromatin accessibility and transcriptional programmes. The degradation of CoREST promoted by KBTBD4 mutation diverts epigenetic programmes inducing significant alterations in transcription to promote increased stemness of cancer cells. Transcriptional analysis of >200 human group 3 and 4 medulloblastomas by RNA-seq, highlights the presence of CoREST and stem-like signatures in tumours with KBTBD4 mutations, which extend to a further sub-set of non-mutant tumours, suggesting CoREST alterations as a novel pathogenetic mechanism of wide relevance in groups 3 and 4. Our findings uncover KBTBD4 mutation as a novel driver of epigenetic reprogramming in non-WNT/non-SHH medulloblastoma, establish a novel mode of tumorigenesis through gain-of-function mutations in ubiquitin ligases (neo-substrate recruitment) and identify both mutant KBTBD4 and CoREST complexes as new druggable targets for improved tumour-specific therapies.
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影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
DOI：
10.15252/embj.201593374
发表时间：
2016-07-01
期刊：
The EMBO journal
影响因子：
--
作者：
Raducu M;Fung E;Serres S;Infante P;Barberis A;Fischer R;Bristow C;Thézénas ML;Finta C;Christianson JC;Buffa FM;Kessler BM;Sibson NR;Di Marcotullio L;Toftgård R;D'Angiolella V
通讯作者：
D'Angiolella V
影响因子：
8.4
作者：
Choi, Seung Ah;Lee, Ji Yeoun;Kim, Seung-Ki
通讯作者：
Kim, Seung-Ki
影响因子：
64.8
作者：
Lee, MG;Wynder, C;Shiekhattar, R
通讯作者：
Shiekhattar, R
DOI：
10.1042/bj20140153
发表时间：
2014-06-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Schumacher FR;Sorrell FJ;Alessi DR;Bullock AN;Kurz T
通讯作者：
Kurz T