Oncogenic KRAS represses the dependence receptor UNC5C via ERK2-FOS signaling in non-small cell lung cancer

KRAS mutation is one of the most prevalent oncogenic driver mutations in NSCLC. UNC5C, as a member of dependence receptors of netrin-1, is a conditional tumor suppressor in cancer progression and metastasis via inducing apoptosis. Despite UNC5C has been intensively reported to be downregulated in multiple types of malignancies, the mechanism of UNC5C loss or downregulation in cancer remains unclear. In this study, we identified UNC5C as a downstream effector of oncogenic KRAS signaling pathway. We found that oncogenic KRAS suppressed UNC5C and inhibition of oncogenic KRAS upregulated UNC5C in KRAS-mutant NSCLC. Mechanically, oncogenic KRAS-mediated downregulation of UNC5C was dependent on the activation of the RAF/MEK/ERK cascade rather than the PI3K/AKT/mTOR pathway. More specifically, ERK2, but not ERK1, was involved in the control of UNC5C expression. Critically, FOS, a downstream transcription factor of the ERK pathway, was responsible for the transcriptional repression of UNC5C in KRAS-mutant NSCLC. In addition, UNC5C, rather than other dependence receptors of netrin-1, was most strongly downregulated in NSCLC and functioned as a tumor suppressor. In conclusion, we reported oncogenic KRAS-mediated transcriptional suppression of UNC5C and deciphered the exact underlying molecular mechanism in NSCLC, thus providing novel insights into the interplay between oncogenes and tumor suppressor genes in KRAS-driven NSCLC.