Mutant p53 driven-LINC00857, a protein scaffold between FOXM1 and deubiquitinase OTUB1, promotes the metastasis of pancreatic cancer
Mutant p53 driven-LINC00857, a protein scaffold between FOXM1 and deubiquitinase OTUB1, promotes the metastasis of pancreatic cancer
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突变p53驱动的LINC00857是FOXM1和去泛素化酶OTUB1之间的蛋白支架，促进胰腺癌的转移
DOI：
10.1016/j.canlet.2022.215976
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发表时间：
2022
期刊：
影响因子：
9.7
通讯作者：
Zheng Wang
中科院分区：
文献类型：
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作者：
Weifan Zhang;Weikun Qian;Jingtao Gu;Mengyuan Gong;Wunai Zhang;Simei Zhang;Cancan Zhou;Zhengdong Jiang;Jie Jiang;Liang Han;Xiaoqin Wang;Zheng Wu;Qingyong Ma;Zheng Wang
肿瘤转移是胰腺癌患者复发和死亡的主要不利因素。P53突变被认为是PC中第二常见的突变类型，并显着促进PC转移。然而，p53突变的分子机制，特别是蛋白质与长链非编码RNA（lncRNA）的调控关系，仍然不清楚。在本研究中，我们证明了lncRNA LINC 00857在PC中表现出显著升高的水平，并且与预后不良相关;此外，TCGA数据显示，与野生型p53组相比，突变型p53组中LINC 00857的表达显著上调。功能获得和丧失实验表明LINC 00857促进PC细胞的转移。我们进一步发现LINC 00857上调FOXM 1蛋白表达，从而加速体外和体内转移。在机制上，LINC 00857同时与FOXM 1和去泛素化酶OTUB 1结合，从而充当蛋白质支架并增强FOXM 1和OTUB 1之间的相互作用，这通过泛素-蛋白酶体途径抑制FOXM 1降解。有趣的是，我们发现突变型p53通过结合其启动子区域来促进LINC 00857的转录。最后，阿托伐他汀，一种常用的降脂药物，似乎通过抑制突变型p53-LINC 00857轴来抑制PC转移。综上所述，我们的研究结果为生物学驱动PC转移提供了新的见解，并表明突变型p53-LINC 00857轴可能代表PC转移的新治疗靶点。
Tumour metastasis is the major adverse factor for recurrence and death in pancreatic cancer (PC) patients. P53 mutations are considered to be the second most common type of mutation in PC and significantly promote PC metastasis. However, the molecular mechanisms underlying the effects of p53 mutations, especially the regulatory relationship of the protein with long noncoding RNAs (lncRNAs), remain unclear. In the present study, we demonstrated that the lncRNA LINC00857 exhibits a significantly elevated level in PC and that it is associated with poor prognosis; furthermore, TCGA data showed that LINC00857 expression was significantly upregulated in the mutant p53 group compared with the wild-type p53 group. Gain- and loss-of-function experiments showed that LINC00857 promotes the metastasis of PC cells. We further found that LINC00857 upregulates FOXM1 protein expression and thus accelerates metastasis in vitro and in vivo. Mechanistically, LINC00857 bound simultaneously to FOXM1 and to the deubiquitinase OTUB1, thereby serving as a protein scaffold and enhancing the interaction between FOXM1 and OTUB1, which inhibits FOXM1 degradation through the ubiquitin–proteasome pathway. Interestingly, we found that mutant p53 promotes LINC00857 transcription by binding to its promoter region. Finally, atorvastatin, a commonly prescribe lipid-lowering drug, appeared to inhibit PC metastasis by inhibiting the mutant p53-LINC00857 axis. Taken together, our results provide new insights into the biology driving PC metastasis and indicate that the mutant p53-LINC00857 axis might represent a novel therapeutic target for PC metastasis.