AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis.
AMPK induces degradation of the transcriptional repressor PROX1 impairing branched amino acid metabolism and tumourigenesis.
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AMPK 诱导转录抑制因子 PROX1 降解，损害支链氨基酸代谢和肿瘤发生
DOI：
10.1038/s41467-022-34747-y
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发表时间：
2022-11-24
影响因子：
16.6
通讯作者：
Liu, Yanfeng
中科院分区：
文献类型：
--
作者：
Wang, Yanan;Luo, Mengjun;Wang, Fan;Tong, Yu;Li, Linfeng;Shu, Yu;Qiao, Ke;Zhang, Lei;Yan, Guoquan;Liu, Jing;Ji, Hongbin;Xie, Youhua;Zhang, Yonglong;Gao, Wei-Qiang;Liu, Yanfeng
Tumour cell metabolic plasticity is essential for tumour progression and therapeutic responses, yet the underlying mechanisms remain poorly understood. Here, we identify Prospero-related homeobox 1 (PROX1) as a crucial factor for tumour metabolic plasticity. Notably, PROX1 is reduced by glucose starvation or AMP-activated protein kinase (AMPK) activation and is elevated in liver kinase B1 (LKB1)-deficient tumours. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK enhances the recruitment of CUL4-DDB1 ubiquitin ligase to promote PROX1 degradation. Downregulation of PROX1 activates branched-chain amino acids (BCAA) degradation through mediating epigenetic modifications and inhibits mammalian target-of-rapamycin (mTOR) signalling. Importantly, PROX1 deficiency or Ser79 phosphorylation in liver tumour shows therapeutic resistance to metformin. Clinically, the AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that deficiency of the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signalling, and facilitating tumourigenesis and aggressiveness.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
LKB1 失活会引发氧化还原失衡，从而调节非小细胞肺癌的可塑性和治疗反应。
影响因子：
50.3
作者：
Li F;Han X;Li F;Wang R;Wang H;Gao Y;Wang X;Fang Z;Zhang W;Yao S;Tong X;Wang Y;Feng Y;Sun Y;Li Y;Wong KK;Zhai Q;Chen H;Ji H
通讯作者：
Ji H
DOI：
10.1073/pnas.0337639100
发表时间：
2003-02-18
影响因子：
11.1
作者：
Czubryt, MP;McAnally, J;Olson, EN
通讯作者：
Olson, EN
影响因子：
56.9
作者：
Cipponi, Arcadi;Goode, David L.;Thomas, David M.
通讯作者：
Thomas, David M.
DOI：
10.1097/nen.0b013e3181ca4767
发表时间：
2010-02-01
影响因子：
3.2
作者：
Elsir, Tarnador;Eriksson, Anna;Nister, Momca
通讯作者：
Nister, Momca