Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.
Inactivation of the tumor suppressor p53 by long noncoding RNA RMRP.
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长链非编码 RNA RMRP 灭活肿瘤抑制因子 p53
DOI：
10.1073/pnas.2026813118
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发表时间：
2021-07-20
影响因子：
11.1
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Chen Y;Hao Q;Wang S;Cao M;Huang Y;Weng X;Wang J;Zhang Z;He X;Lu H;Zhou X
抑癌基因p53可以阻止肿瘤的发生，而p53的失活则会促进癌症的发展和耐药性。在这里，我们确定了一个长的非编码RNA，线粒体RNA加工核糖核酸内切酶（RMRP）的RNA组分，通过抑制p53活性促进结直肠癌细胞的生长和增殖。在机制上，RMRP将SNRPA 1保留在细胞核中，从而防止其溶酶体降解。核SNRPA 1然后促进MDM 2介导的p53泛素化和降解。值得注意的是，RMRP的表达是由聚（ADP-核糖）聚合酶（PARP）抑制剂，一组靶向抗癌药物，通过转录因子C/EBPβ诱导的。靶向RMRP通过重新激活p53显著增强结直肠癌细胞对PARP抑制的敏感性。我们的研究提供了肿瘤对PARP抑制剂耐药的可能机制。p53失活与肿瘤发生和耐药性高度相关。在这里，我们确定了一个很长的非编码RNA，线粒体RNA加工核糖核酸内切酶（RMRP）的RNA组分，作为p53的抑制剂。RMRP过表达与结直肠癌预后不良相关。异位RMRP通过促进MDM 2诱导的p53泛素化和降解来抑制p53活性，而RMRP的耗尽激活p53通路。RMRP还在体外和体内以p53依赖的方式促进结直肠癌的生长和增殖。RMRP的这种抗p53作用通过鉴定的伴侣蛋白SNRPA 1执行。RMRP可以与SNRPA 1相互作用并将其隔离在细胞核中，从而通过分子伴侣介导的自噬阻断其溶酶体蛋白水解。核SNRPA 1然后与p53相互作用并增强MDM 2诱导的p53蛋白酶体降解。值得注意的是，SNRPA 1的消融完全消除了RMRP对p53和肿瘤细胞生长的调节，表明SNRPA 1对于RMRP的抗p53功能是不可缺少的。有趣且重要的是，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通过阻止p53活化赋予肿瘤对PARP抑制的抗性。总之，我们的研究表明，RMRP通过SNRPA 1使p53失活而在结直肠癌中发挥致癌作用。
Significance The tumor suppressor p53 prevents tumorigenesis, while inactivation of p53 promotes cancer development and drug resistance. Here, we identify that a long noncoding RNA, the RNA component of mitochondrial RNA-processing endoribonuclease (RMRP), promotes growth and proliferation of colorectal cancer cells by inhibiting p53 activity. Mechanistically, RMRP retains SNRPA1 in the nucleus, thus preventing its lysosomal degradation. The nuclear SNRPA1 then prompts MDM2-mediated p53 ubiquitination and degradation. Remarkably, RMRP expression is induced by poly (ADP-ribose) polymerase (PARP) inhibitors, a group of targeted anticancer drugs, through the transcription factor C/EBPβ. Targeting RMRP significantly enhances sensitivity of colorectal cancer cells to PARP inhibition by reactivating p53. Our study provides a possible mechanism underling tumor resistance to PARP inhibitors. 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.