Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
The University of Texas Graduate School of Biomedical Sciences Houston, Houston, TX, 77030, USA.
Nat Commun. 2019 Sep 25;10(1):4363. doi: 10.1038/s41467-019-12377-1.
The LKB1/AMPK pathway plays a major role in cellular homeostasis and tumor suppression. Down-regulation of LKB1/AMPK occurs in several human cancers and has been implicated in metabolic diseases. However, the precise upstream regulation of LKB1-AMPK pathway is largely unknown. Here, we report that AMPK activation by LKB1 is regulated by tankyrases. Tankyrases interact with and ribosylate LKB1, promoting its K63-linked ubiquitination by an E3 ligase RNF146, which blocks LKB1/STRAD/MO25 complex formation and LKB1 activation. LKB1 activation by tankyrase inhibitors induces AMPK activation and suppresses tumorigenesis. Similarly, the tankyrase inhibitor G007-LK effectively regulates liver metabolism and glycemic control in diabetic mice in a LKB1-dependent manner. In patients with lung cancer, tankyrase levels negatively correlate with p-AMPK levels and poor survival. Taken together, these findings suggest that tankyrase and RNF146 are major up-stream regulators of LKB1-AMPK pathway and provide another focus for cancer and metabolic disease therapies.
LKB1/AMPK 通路在细胞稳态和肿瘤抑制中起着重要作用。几种人类癌症中 LKB1/AMPK 的下调已被证实与代谢疾病有关。然而，LKB1-AMPK 通路的精确上游调控仍知之甚少。在这里，我们报告 LKB1 通过 tankyrases 激活 AMPK。Tankyrases 与 LKB1 相互作用并使其发生核糖体酰化，促进其被 E3 连接酶 RNF146 进行 K63 连接的泛素化，从而阻断 LKB1/STRAD/MO25 复合物的形成和 LKB1 的激活。Tankyrase 抑制剂激活 LKB1 可诱导 AMPK 激活并抑制肿瘤发生。同样，tankyrase 抑制剂 G007-LK 以 LKB1 依赖性方式有效调节糖尿病小鼠的肝脏代谢和血糖控制。在肺癌患者中，tankyrase 水平与 p-AMPK 水平呈负相关，与预后不良相关。综上所述，这些发现表明 tankyrase 和 RNF146 是 LKB1-AMPK 通路的主要上游调控因子，为癌症和代谢疾病的治疗提供了另一个重点。
