STK11 Prevents Invasion through Signal Transducer and Activator of Transcription 3/5 and FAK Repression in Cutaneous Melanoma

The STK11/LKB1 is a tumor suppressor involved in metabolism and cell motility. In BRAF V-600E melanoma, STK11 is inactivated by extracellular signal.regulated kinase and RSK, preventing it from binding and activating adenosine monophosphate-activated protein kinase and promoting melanoma cell proliferation. Although STK11 mutations occur in 5.10% of cutaneous melanoma, few functional studies have been performed. By knocking out STK11 with CRISPR/Cas9 in two human BRAF-mutant melanoma cell lines, we found that STK11 loss reduced the sensitivity to a BRAF inhibitor. More strikingly, STK11 loss led to an increased invasive phenotype in both three-dimensional spheroids and in vivo zebrafish xenograft models. STK11 overexpression consistently reversed the invasive phenotype. Interestingly, STK11 knockout increased invasion also in an NRAS-mutant melanoma cell line. Furthermore, although STK11 was expressed in primary human melanoma tumors, its expression significantly decreased in melanoma metastases, especially in brain metastases. In the STK11-knockout cells, we observed increased activating phosphorylation of signal transducer and activator of transcription 3/5 and FAK. Using inhibitors of signal transducer and activator of transcription 3/5 and FAK, we reversed the invasive phenotype in both BRAF- and NRAS-mutated cells. Our findings confirm an increased invasive phenotype on STK11 inactivation in BRAF- and NRAS-mutant cutaneous melanoma that can be targeted by signal transducer and activator of transcription 3/5 and FAK inhibition.

Automated summary

Inactivation of STK11 in BRAF and NRAS-mutant melanoma leads to increased proliferation and invasive phenotype. Overexpression of STK11 reverses this invasive phenotype and can be targeted by inhibitors of signal transducer and activator of transcription 3/5 and FAK.