Abstract
Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here, we show that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes.
Highlights
Lung cancer is one of the most deadly diseases worldwide, mainly attributing to the high frequency of metastasis [1]
We discover an important novel pathway involved in lung cancer progression and metastasis triggered by LKB1 loss: LKB1 loss triggers the nuclear translocation of CRTC1, which in turn upregulates NEDD9 and promotes lung cancer progression and metastasis
Our study highlights NEDD9 as an important downstream mediator in lung cancer progression evoked by LKB1 loss
Summary
Lung cancer is one of the most deadly diseases worldwide, mainly attributing to the high frequency of metastasis [1]. The molecules mediating lung cancer progression and metastasis triggered by LKB1 loss remain elusive. Identifying such mediators and deciphering the underlying mechanism are important for better understanding the Authors' Affiliations: 1State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology; 2Institute of Neuroscience and State Key Laboratory of Neuroscience; 3Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences; 4Department of Thoracic Surgery, Fudan University Shanghai Cancer Center; 5Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; and 6Department of Medicine, Massachusetts General Hospital Cancer Center, and 7Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
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