长非编码 RNA RMRP 使抑癌基因 p53 失活。

Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.

机构信息

Fudan University Shanghai Cancer Center, Fudan University, Shanghai 200032, China.

Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

出版信息

Proc Natl Acad Sci U S A. 2021 Jul 20;118(29). doi: 10.1073/pnas.2026813118.

DOI:10.1073/pnas.2026813118

PMID:34266953

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8307289/

Abstract

p53 inactivation is highly associated with tumorigenesis and drug resistance. Here, we identify a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), as an inhibitor of p53. RMRP is overexpressed and associated with an unfavorable prognosis in colorectal cancer. Ectopic RMRP suppresses p53 activity by promoting MDM2-induced p53 ubiquitination and degradation, while depletion of RMRP activates the p53 pathway. RMRP also promotes colorectal cancer growth and proliferation in a p53-dependent fashion in vitro and in vivo. This anti-p53 action of RMRP is executed through an identified partner protein, SNRPA1. RMRP can interact with SNRPA1 and sequester it in the nucleus, consequently blocking its lysosomal proteolysis via chaperone-mediated autophagy. The nuclear SNRPA1 then interacts with p53 and enhances MDM2-induced proteasomal degradation of p53. Remarkably, ablation of SNRPA1 completely abrogates RMRP regulation of p53 and tumor cell growth, indicating that SNRPA1 is indispensable for the anti-p53 function of RMRP. Interestingly and significantly, poly (ADP-ribose) polymerase (PARP) inhibitors induce RMRP expression through the transcription factor C/EBPβ, and RMRP confers tumor resistance to PARP inhibition by preventing p53 activation. Altogether, our study demonstrates that RMRP plays an oncogenic role by inactivating p53 via SNRPA1 in colorectal cancer.

摘要

p53 失活与肿瘤发生和耐药高度相关。在这里，我们鉴定了一种长非编码 RNA，即线粒体 RNA 加工内切核糖核酸酶 (RMRP) 的 RNA 成分，作为 p53 的抑制剂。RMRP 在结直肠癌中过表达且与不良预后相关。异位 RMRP 通过促进 MDM2 诱导的 p53 泛素化和降解来抑制 p53 活性，而 RMRP 的耗竭则激活 p53 通路。RMRP 还以依赖 p53 的方式在体外和体内促进结直肠癌细胞的生长和增殖。RMRP 的这种抗 p53 作用是通过鉴定的伙伴蛋白 SNRPA1 执行的。RMRP 可以与 SNRPA1 相互作用并将其隔离在核内，从而通过伴侣介导的自噬阻止其溶酶体蛋白水解。然后核内 SNRPA1 与 p53 相互作用并增强 MDM2 诱导的 p53 蛋白酶体降解。值得注意的是，SNRPA1 的缺失完全消除了 RMRP 对 p53 和肿瘤细胞生长的调控作用，表明 SNRPA1 是 RMRP 抗 p53 功能所必需的。有趣的是，聚（ADP-核糖）聚合酶（PARP）抑制剂通过转录因子 C/EBPβ 诱导 RMRP 表达，并且 RMRP 通过防止 p53 激活赋予肿瘤对 PARP 抑制的耐药性。总之，我们的研究表明，RMRP 通过 SNRPA1 在结直肠癌中失活 p53 发挥致癌作用。