Center for Translational Medicine, The Affiliated Zhangjiagang Hospital of Soochow University, Suzhou Medical College of Soochow University, 68 Jiyang West Road, Suzhou 215600, China.
School of Life Science and Technology, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.
Cell Rep. 2023 Aug 29;42(8):112833. doi: 10.1016/j.celrep.2023.112833. Epub 2023 Jul 23.
The p53 tumor suppressor exerts antitumor functions through its ability to regulate the transcription of its downstream targets. Long noncoding RNAs (lncRNAs) act as oncogenes or tumor suppressors implicated in tumorigenesis and tumor progression. Here, we identify the lncRNA LINC00324 (long intergenic noncoding RNA 00324) as a direct p53 transcriptional target. Knockdown of LINC00324 expression promotes tumor growth by reducing p53 transcriptional activity, whereas ectopic LINC00324 expression demonstrates a reverse effect. Notably, LINC00324 is present in the endogenous p53 complex in tumor cells and directly binds to the C-terminal domain of p53 in vitro. Mechanistically, LINC00324 enables p53 transactivation by competitively disrupting the p53-SET interaction, resulting in an increase of p300/CBP-mediated H3K18 and H3K27 acetylation on the p53 target promoters. Lower LINC00324 expression is associated with more aggressive disease status and predicts worse overall survival of patients with cancer. Our study identifies a p53/LINC00324 positive feedback loop that suppresses tumor growth by counteracting SET-mediated transcriptional repression.
抑癌基因 p53 通过调节其下游靶基因的转录来发挥抗肿瘤作用。长链非编码 RNA（lncRNA）可作为癌基因或肿瘤抑制因子参与肿瘤发生和肿瘤进展。在这里，我们确定 lncRNA LINC00324（长基因间非编码 RNA 00324）为 p53 的直接转录靶标。LINC00324 表达的敲低通过降低 p53 转录活性促进肿瘤生长，而异位 LINC00324 表达则表现出相反的效果。值得注意的是，LINC00324 存在于肿瘤细胞中的内源性 p53 复合物中，并在体外直接与 p53 的 C 端结构域结合。在机制上，LINC00324 通过竞争性破坏 p53-SET 相互作用来实现 p53 的反式激活，导致 p300/CBP 介导的 p53 靶启动子上 H3K18 和 H3K27 乙酰化增加。LINC00324 的表达降低与疾病侵袭性更强相关，并预测癌症患者的总生存率更差。我们的研究确定了一个 p53/LINC00324 正反馈回路，通过抵消 SET 介导的转录抑制来抑制肿瘤生长。
