Wang Yan, Zhang Xiong-Fei, Wang Dong-Yan, Zhu Yi, Chen Lei, Zhang Jing-Jing
Endoscopy Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, People's Republic of China.
Department of Biochemistry, Nanjing University of Chinese Medicine, Nanjing, 210023, People's Republic of China.
Cell Death Discov. 2021 Sep 22;7(1):261. doi: 10.1038/s41420-021-00640-8.
Pancreatic cancer is a highly aggressive and lethal digestive system malignancy. Our previous studies revealed the correlation of high levels of lncRNA SOX2OT expression with patients' poor survival outcomes, the promoting role of SOX2OT in proliferation and cycle progression of pancreatic cancer cells, and the in vivo binding of SOX2OT to RNA binding protein FUS, which destabilized the protein expression of FUS. However, the mechanism of SOX2OT binding and inhibiting FUS protein stability remains unclear. In this study, we performed RNA pull-down, cycloheximide-chase, and ubiquitination assays to determine the effect of SOX2OT on FUS ubiquitination, and explored the specific regulatory mechanism of SOX2OT-FUS axis in pancreatic cancer cell migration, invasion, in vivo tumor growth, and metastasis through RNA sequencing. We found that SOX2OT binds to FUS through its 5' and 3' regions, resulting in FUS ubiquitination and degradation. The SOX2OT-FUS regulatory axis promotes migration, invasion, tumor growth, and metastasis ability of pancreatic cancer cells. The in-depth elaboration of the SOX2OT-FUS regulatory axis in pancreatic cancer may clarify the mechanism of action of SOX2OT and provide new ideas for pancreatic cancer treatment.
胰腺癌是一种极具侵袭性和致死性的消化系统恶性肿瘤。我们之前的研究揭示了长链非编码RNA SOX2OT的高表达水平与患者不良生存结局的相关性、SOX2OT在胰腺癌细胞增殖和细胞周期进程中的促进作用，以及SOX2OT在体内与RNA结合蛋白FUS的结合，这使FUS的蛋白表达不稳定。然而，SOX2OT结合并抑制FUS蛋白稳定性的机制仍不清楚。在本研究中，我们进行了RNA下拉、放线菌酮追踪和泛素化实验，以确定SOX2OT对FUS泛素化的影响，并通过RNA测序探索SOX2OT-FUS轴在胰腺癌细胞迁移、侵袭、体内肿瘤生长和转移中的具体调控机制。我们发现SOX2OT通过其5'和3'区域与FUS结合，导致FUS泛素化和降解。SOX2OT-FUS调控轴促进胰腺癌细胞的迁移、侵袭、肿瘤生长和转移能力。深入阐述胰腺癌中SOX2OT-FUS调控轴可能会阐明SOX2OT的作用机制，并为胰腺癌治疗提供新思路。
