Division of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USA.
Division of Translational Oncology, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10128, USA.
Cell Rep. 2021 Jun 29;35(13):109329. doi: 10.1016/j.celrep.2021.109329.
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.
许多长非编码 RNA (lncRNA) 基因存在于与癌症相关的基因座附近，但缺乏将 lncRNA 功能与癌症中反复出现的遗传改变联系起来的证据。在这里，我们报告说，DINO 是从与癌症相关的 DINO/CDKN1A 基因座转录的 lncRNA，它独立于编码该基因座的蛋白质 p21 抑制肿瘤形成。Dino 缺失一个或两个等位基因会损害 p53 信号转导和细胞凋亡，导致遗传定义的肿瘤发生小鼠模型中出现杂合不足的肿瘤抑制表型。DINO/CDKN1A 基因座的一个离散区域在人类癌症中经常发生过度甲基化，沉默 DINO 但不沉默 CDKN1A，后者编码 p21。过度甲基化沉默 DINO，在转录中损害 p53 信号通路，与 TP53 改变互斥，表明 DINO 和 TP53 构成一个共同的肿瘤抑制模块。因此，DINO 编码一种 lncRNA，对肿瘤抑制至关重要，它在人类癌症中经常被沉默，作为逃避 p53 依赖性肿瘤抑制的一种机制。
