Mutant p53 driven-LINC00857, a protein scaffold between FOXM1 and deubiquitinase OTUB1, promotes the metastasis of pancreatic cancer

• Published in: Cancer letters 2023-01, Vol.552, p.215976-215976, Article 215976
• Main Authors: Zhang, Weifan, Qian, Weikun, Gu, Jingtao, Gong, Mengyuan, Zhang, Wunai, Zhang, Simei, Zhou, Cancan, Jiang, Zhengdong, Jiang, Jie, Han, Liang, Wang, Xiaoqin, Wu, Zheng, Ma, Qingyong, Wang, Zheng
• Format: Article
• Language: English
• Subjects: Antibodies; Atorvastatin; Cell Line, Tumor; Cell Proliferation; Deubiquitinating Enzymes - genetics; Deubiquitinating Enzymes - metabolism; Forkhead Box Protein M1 - genetics; Forkhead Box Protein M1 - metabolism; FOXM1; Gene Expression Regulation, Neoplastic; Humans; LINC00857; Metastases; Metastasis; Molecular modelling; Mutant p53; Mutants; Mutation; Non-coding RNA; OTUB1; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms; Pancreatic Neoplasms - pathology; Pheochromocytoma cells; Proteasomes; Proteins; RNA, Long Noncoding - genetics; Therapeutic targets; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Ubiquitin; Wound healing
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215976

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. •LINC00857 significantly promotes pancreatic cancer metastasis, which is dependent on the transcription factor FOXM1.•LINC00857 enhances the interaction between FOXM1 and OTUB1, which inhibit FOXM1 degradation by deubiquitination pathway.•Mutant p53 promotes LINC00857 transcription, thereby triggering the high expression of LINC00857 in pancreatic cancer.•Mutant p53-LINC00857 axis is blocked by atorvastatin, which provides a therapeutic strategy for panccreatic cancer.