Most inactivating mutations in TP53 gene generates neomorphic forms of p53 proteins that experimental evidence and clinical observations suggest to exert gain-of-function effects. While massive effort has been deployed in the dissection of wild type p53 transcriptional programme, p53 mutant pro-tumorigenic gene network is still largely elusive. To help dissecting the molecular basis of p53 mutant GOF, we performed an analysis of a fully annotated genomic and transcriptomic human pancreatic adenocarcinoma to select candidate players of p53 mutant network on the basis their differential expression between p53 mutant and p53 wild-type cohorts and their prognostic value. We identified NUAK2 and RCan2 whose p53 mutant GOF-dependent regulation was further validated in pancreatic cancer cellular model. Our data demonstrated that p53R270H can physically bind RCan2 gene locus in regulatory regions corresponding to the chromatin permissive areas where known binding partners of p53 mutant, such as p63 and Srebp, bind. Overall, starting from clinically relevant data and progressing into experimental validation, our work suggests NUAK2 and RCan2 as novel candidate players of the p53 mutant pro-tumorigenic network whose prognostic and therapeutic interest might attract future studies.

中文翻译：

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NUAK2 和 RCan2 参与 p53 突变体促肿瘤网络

TP53 基因中的大多数失活突变会产生新形态的 p53 蛋白，实验证据和临床观察表明这些蛋白会产生功能获得效应。虽然在解析野生型 p53 转录程序方面已经付出了巨大的努力，但 p53 突变体促肿瘤基因网络仍然在很大程度上难以捉摸。为了帮助剖析 p53 突变 GOF 的分子基础，我们对完全注释的基因组和转录组人类胰腺腺癌进行了分析，以根据 p53 突变体和 p53 野生型队列之间的差异表达以及它们的差异表达来选择 p53 突变网络的候选参与者。预后价值。我们鉴定了 NUAK2 和 RCan2，其 p53 突变体 GOF 依赖性调节在胰腺癌细胞模型中得到进一步验证。我们的数据表明，p53R270H 可以在与染色质允许区域相对应的调控区域中物理结合 RCan2 基因位点，其中 p53 突变体的已知结合配偶体，例如 p63 和 Srebp，结合。总体而言，从临床相关数据开始并进入实验验证，我们的工作表明 NUAK2 和 RCan2 作为 p53 突变体促肿瘤发生网络的新候选参与者，其预后和治疗兴趣可能会吸引未来的研究。