DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2  

作　　者：Gang Zhao Hang Yuan Qin Li Jie Zhang Yafei Guo Tianyu Feng Rui Gu Deqiong Ou Siqi Li Kai Li Ping Lin 

机构地区：[1]Lab of Experimental Oncology,State Key Laboratory of Biotherapy and Cancer Center,and Frontiers Science Center for Disease-Related Molecular Network,West China Hospital,Sichuan University,Chengdu,Sichuan 610041,China

出　　处：《Signal Transduction and Targeted Therapy》2022年第9期3536-3550,共15页信号转导与靶向治疗（英文）

基　　金：This work was supported by the National Natural Science Foundation of China(81874071,81773756,82103525,and 82072933);1.3.5 project for disciplines of ecellence-Clinical Research Incubation Project,West China Hospital,Sichuan University(2020HXFH007);Post-Doctor Research Project,West China Hospital,Sichuan University(2020HXBH036).

摘　　要：Metastasis is a major cause of colorectal cancer(CRC)mortality,but its molecular mechanisms are still not fully understood.Here,we show that upregulated DDX39B correlates with liver metastases and aggressive phenotypes in CRC.DDX39B is an independent prognostic factor associated with poor clinical outcome in CRC patients.We demonstrate that Sp1 potently activates DDX39B transcription by directly binding to the GC box of the DDX39B promoter in CRC cells.DDX39B overexpression augments the proliferation,migration,and invasion of CRC cells,while the opposite results are obtained in DDX39B-deficient CRC cells.Mechanistically,DDX39B interacts directly with and stabilizes PKM2 by competitively suppressing STUB1-mediated PKM2 ubiquitination and degradation.Importantly,DDX39B recruits importin a5 to accelerate the nuclear translocation of PKM2 independent of ERK1/2-mediated phosphorylation of PKM2,leading to the transactivation of oncogenes and glycolysis-related genes.Consequently,DDX39B enhances glucose uptake and lactate production to activate Warburg effect in CRC.We identify that Arg319 of DDX39B is required for PKM2 binding as well as PKM2 nuclear accumulation and for DDX39B to promote CRC growth and metastasis.In addition,blocking PKM2 nuclear translocation or treatment with glycolytic inhibitor 2-deoxy-D-glucose efficiently abolishes DDX39B-triggered malignant development in CRC.Taken together,ourfindings uncover akey role forDDX39B in modulating glycolytic reprogramming and aggressive progression,and implicate DDX39B as a potential therapeutic target in CRC.

关 键 词：PKM2 COLORECTAL INVASION 

分 类 号：R730[医药卫生—肿瘤]