p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.
p53-intact cancers escape tumor suppression through loss of long noncoding RNA Dino.
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DOI：
10.1016/j.celrep.2021.109329
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发表时间：
2021-06-29
期刊：
影响因子：
8.8
通讯作者：
Schmitt AM
中科院分区：
文献类型：
--
作者：
Marney CB;Anderson ES;Adnan M;Peng KL;Hu Y;Weinhold N;Schmitt AM
许多长链非编码RNA（lncRNA）基因存在于癌症相关位点附近，但缺乏将lncRNA功能与癌症中复发性遗传改变联系起来的证据。在这里，我们报告说，DINO，从癌症相关的DINO/CDKN 1A基因座转录的lncRNA，抑制肿瘤的形成独立于p21，在该基因座编码的蛋白质。Dino的一个或两个等位基因的丢失损害p53信号传导和细胞凋亡，导致在遗传定义的肿瘤发生小鼠模型中单倍不足的肿瘤抑制表型。DINO/CDKN 1A基因座的一个离散区域在人类癌症中反复高甲基化，沉默DINO而不是编码p21的基因CDKN 1A。超甲基化使DINO沉默，反式损害p53信号通路，并且与TP 53改变相互排斥，表明DINO和TP 53构成共同的肿瘤抑制模块。因此，DINO编码肿瘤抑制所必需的lncRNA，其在人类癌症中作为逃避p53依赖性肿瘤抑制的机制而反复沉默。肿瘤发生需要逃避p53肿瘤抑制蛋白。尽管p53通路完整，但50%的癌症是如何发展的在很大程度上仍然未知。Marney等人在此报道，lncRNA DINO的缺失提供了p53完整细胞中肿瘤发生的途径，并且DINO在人类癌症中反复沉默。
Many long noncoding RNA (lncRNA) genes exist near cancer-associated loci, yet evidence connecting lncRNA functions to recurrent genetic alterations in cancer are lacking. Here, we report that DINO, the lncRNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation independent of p21, the protein encoded at the locus. Loss of one or two alleles of Dino impairs p53 signaling and apoptosis, resulting in a haplo-insufficient tumor suppressor phenotype in genetically defined mouse models of tumorigenesis. A discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO, impairs p53 signaling pathway in trans, and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a lncRNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression. Tumorigenesis requires escape from the p53 tumor suppressor protein. How 50% of cancers develop despite an intact p53 pathway remains largely unknown. Marney et al. report here that loss of the lncRNA DINO provides a route to tumorigenesis in p53-intact cells, and DINO is recurrently silenced in human cancers.
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影响因子：
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作者：
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影响因子：
50.3
作者：
Hu X;Feng Y;Zhang D;Zhao SD;Hu Z;Greshock J;Zhang Y;Yang L;Zhong X;Wang LP;Jean S;Li C;Huang Q;Katsaros D;Montone KT;Tanyi JL;Lu Y;Boyd J;Nathanson KL;Li H;Mills GB;Zhang L
通讯作者：
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影响因子：
20.3
作者：
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通讯作者：
Bertoni, Francesco
DOI：
10.1073/pnas.1910255116
发表时间：
2019-10-29
影响因子：
11.1
作者：
Klimovich, Boris;Mutlu, Samet;Stiewe, Thorsten
通讯作者：
Stiewe, Thorsten