The AMPK-HOXB9-KRAS axis regulates lung adenocarcinoma growth in response to cellular energy alterations.
The AMPK-HOXB9-KRAS axis regulates lung adenocarcinoma growth in response to cellular energy alterations.
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DOI：
10.1016/j.celrep.2022.111210
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发表时间：
2022-08
期刊：
影响因子：
8.8
通讯作者：
Tianzhuo Wang;Huiying Guo;Qianchen Li;Weijie Wu;Miao Yu;Lei Zhang;Cuicui Li;Jiagui Song
中科院分区：
文献类型：
--
作者：
Tianzhuo Wang;Huiying Guo;Qianchen Li;Weijie Wu;Miao Yu;Lei Zhang;Cuicui Li;Jiagui Song
HOXB 9是与肺腺癌（LUAD）患者的不利结果相关的重要转录因子。然而，其降解机制仍不清楚。在这里，我们表明HOXB 9是AMP激酶α（AMPKα）的底物。AMPK介导HOXB 9 T133磷酸化并下调小鼠和LUAD细胞中HOXB 9的水平。在机制上，磷酸化的HOXB 9促进E3连接酶Praja 2介导的HOXB 9降解。通过消耗AMPKα1/2或使用HOXB 9 T133 A突变体阻断HOXB 9磷酸化通过上调HOXB 9和KRAS（在本文中被鉴定为HOXB 9的靶标）促进细胞培养物和小鼠异种移植物中的肿瘤细胞生长。临床上，LUAD样本中AMPK激活水平与pHOXB 9水平呈正相关;较高的pHOXB 9水平与LUAD患者的较好生存率相关。因此，我们提出了HOXB 9降解机制，并证明了AMPK-HOXB 9-KRAS轴连接葡萄糖水平调节AMPK激活HOXB 9稳定性和KRAS基因表达，最终控制LUAD进展。
HOXB9 is an important transcription factor associated with unfavorable outcomes in patients with lung adenocarcinoma (LUAD). However, its degradation mechanism remains unclear. Here, we show that HOXB9 is a substrate of AMP kinase alpha (AMPKα). AMPK mediates HOXB9 T133 phosphorylation and downregulates the level of HOXB9 in mice and LUAD cells. Mechanistically, phosphorylated HOXB9 promoted E3 ligase Praja2-mediated HOXB9 degradation. Blocking HOXB9 phosphorylation by depleting AMPKα1/2 or employing the HOXB9 T133A mutant promoted tumor cell growth in cell culture and mouse xenografts via upregulation of HOXB9 and KRAS that is herein identified as a target of HOXB9. Clinically, AMPK activation levels in LUAD samples were positively correlated with pHOXB9 levels; higher pHOXB9 levels were associated with better survival of patients with LUAD. We thus present a HOXB9 degradation mechanism and demonstrate an AMPK-HOXB9-KRAS axis linking glucose-level-regulated AMPK activation to HOXB9 stability and KRAS gene expression, ultimately controlling LUAD progression.