FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth.,Cell Death & Disease

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FBXO22 mediates polyubiquitination and inactivation of LKB1 to promote lung cancer cell growth.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-06-19 , DOI: 10.1038/s41419-019-1732-9
Xiao-Na Zhu ₁ , Ping He ₁ , Liang Zhang ₁ , Shuo Yang ₁ , Hui-Lin Zhang ₁ , Di Zhu ₁ , Meng-Di Liu ₁ , Yun Yu ₁

Affiliation

Liver kinase B1 (LKB1) regulates both cell growth and energy metabolism. Inactivated mutations of LKB1, observed in 20-30% of nonsmall cell lung cancers (NSCLC), contribute significantly to lung cancer malignancy progression. However, the upstream signalings regulating LKB1 activity remain incompletely understood. Here, we present evidence that FBXO22 interacts with and promotes polyubiquitination of LKB1. More intriguingly, FBXO22 mediates Lys-63-linked LKB1 polyubiquitination and inhibits kinase activity of LKB1. Furthermore, over-expression of FBXO22 promotes NSCLC cell growth through inhibiting LKB1-AMPK-mTOR signaling in vitro and in vivo. Clinically, FBXO22 is highly expressed in human lung adenocarcinoma and high FBXO22 expression predicts significant poor prognosis. Our study provides new insights into the upstream regulation of LKB1 activation and identifies FBXO22 as a potential therapeutic target for lung cancer treatment.

中文翻译：

FBXO22介导LKB1的多聚泛素化和失活以促进肺癌细胞的生长。

肝激酶B1（LKB1）调节细胞生长和能量代谢。在20％至30％的非小细胞肺癌（NSCLC）中观察到的LKB1失活突变，对肺癌的恶性进展有重要作用。但是，调节LKB1活性的上游信号仍然不完全了解。在这里，我们提供了FBXO22与LKB1相互作用并促进LKB1的多聚泛素化的证据。更有趣的是，FBXO22介导Lys-63连接的LKB1多聚泛素化并抑制LKB1的激酶活性。此外，FBXO22的过表达通过在体外和体内抑制LKB1-AMPK-mTOR信号传导来促进NSCLC细胞的生长。临床上，FBXO22在人肺腺癌中高表达，而FBXO22高表达预示着明显的不良预后。

更新日期：2019-06-19

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