LKB1 Regulates an AMPK-Independent Kinase Cascade to Suppress Metastasis

Loss of serine/threonine kinase 11 (STK11, also known as LKB1) drives tumor initiation and metastasis in multiple cancer types. LKB1 acts as a tumor suppressor by regulating metabolism and cell growth via activation of AMP-activated protein kinase (AMPK). However, it is unknown which effectors of LKB1 are required for its ability to prevent metastasis. Goodwin and colleagues characterized the regulation of epithelial-to-mesenchymal transition (EMT) factors in LKB1-deficient tumor cell lines and found that suppression of LKB1 resulted in increased protein levels of the EMT transcription factor SNAIL1. Depletion of MAP/microtubule affinity-regulating kinase 1 (MARK1) or MARK4, both direct substrates of LKB1, mimicked the deleterious effects of LKB1 loss on SNAIL1 expression, whereas knockdown of AMPK did not affect SNAIL1. In silico analysis of MARK1/4 substrates identified the scaffold protein DIX domain-containing 1 (DIXDC1), and silencing of DIXDC1 or mutation of the MARK1/4 phosphorylation site Ser592 upregulated SNAIL1 expression. Phosphorylation of DIXDC1 Ser592 resulted in its localization to focal adhesions, where it contributed to focal adhesion maturation; mutation or depletion of DIXDC1 impaired this maturation process and triggered hyperactivation of focal adhesion kinase (FAK), which stimulated the RAS–MEK–ERK signaling cascade and downstream SNAIL1 expression. Phenotypically, loss of LKB1 or DIXDC1 increased cell migration and invasion, suggesting that LKB1 negatively regulates metastatic potential through MARK1/4 and DIXDC1. Indeed, silencing or mutation of DIXDC1 in lung adenocarcinoma cell lines increased metastatic colonization and tumor burden in vivo, similar to the effect of LKB1 loss. Furthermore, DIXDC1 expression positively correlated with progression-free survival and overall survival in patients with lung adenocarcinoma, and DIXDC1 was frequently deleted in multiple tumor types. These data define an AMPK-independent signaling pathway by which LKB1 suppresses metastasis and identify DIXDC1 as an endogenous inhibitor of EMT in human cancer.

Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk BE, Shaw RJ. An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls SNAIL1 and metastatic potential. Mol Cell 2014 Jul 17 [Epub ahead of print].

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