DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2.
DDX39B drives colorectal cancer progression by promoting the stability and nuclear translocation of PKM2.
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DDX39B 通过促进 PKM2 的稳定性和核转位来驱动结直肠癌进展
DOI：
10.1038/s41392-022-01096-7
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发表时间：
2022-08-17
影响因子：
39.3
通讯作者：
Lin, Ping
中科院分区：
文献类型：
--
作者：
Zhao, Gang;Yuan, Hang;Li, Qin;Zhang, Jie;Guo, Yafei;Feng, Tianyu;Gu, Rui;Ou, Deqiong;Li, Siqi;Li, Kai;Lin, Ping
转移是结直肠癌（CRC）死亡的主要原因，但其分子机制尚不完全清楚。在这里，我们发现上调的DDX39B与CRC的肝转移和侵袭性表型相关。DDX39B是与CRC患者临床预后不良相关的独立预后因素。在结直肠癌细胞中，Sp1通过直接结合DDX39B启动子的GC盒，有效激活DDX39B的转录。DDX39B过表达增强了CRC细胞的增殖、迁移和侵袭，而DDX39B缺失的CRC细胞则相反。在机制上，DDX39B通过竞争性地抑制stub1介导的PKM2泛素化和降解，直接与PKM2相互作用并稳定PKM2。重要的是，DDX39B招募输入蛋白α5加速PKM2的核易位，而不依赖于erk1 /2介导的PKM2磷酸化，从而导致癌基因和糖酵解相关基因的反激活。因此，DDX39B增加葡萄糖摄取和乳酸生成，激活结直肠癌中的Warburg效应。我们发现DDX39B的Arg319是PKM2结合和PKM2核积累所必需的，也是DDX39B促进结直肠癌生长和转移所必需的。此外，阻断PKM2核易位或糖酵解抑制剂2-脱氧-d -葡萄糖治疗可有效消除ddx39b引发的结直肠癌恶性发展。综上所述，我们的研究结果揭示了DDX39B在调节糖酵解重编程和侵袭性进展中的关键作用，并暗示DDX39B是CRC的潜在治疗靶点。
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 α5 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, our findings uncover a key role for DDX39B in modulating glycolytic reprogramming and aggressive progression, and implicate DDX39B as a potential therapeutic target in CRC.
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影响因子：
9
作者：
He C;Li A;Lai Q;Ding J;Yan Q;Liu S;Li Q
通讯作者：
Li Q
影响因子：
14.9
作者：
Gromadzka AM;Steckelberg AL;Singh KK;Hofmann K;Gehring NH
通讯作者：
Gehring NH
影响因子：
3.8
作者：
Böckelman C;Beilmann-Lehtonen I;Kaprio T;Koskensalo S;Tervahartiala T;Mustonen H;Stenman UH;Sorsa T;Haglund C
通讯作者：
Haglund C
影响因子：
37.3
作者：
Hsu MC;Hung WC
通讯作者：
Hung WC
影响因子：
64.5
作者：
Hsu, Peggy P.;Sabatini, David M.
通讯作者：
Sabatini, David M.