Journal
ONCOGENE
Volume 41, Issue 2, Pages 293-300Publisher
SPRINGERNATURE
DOI: 10.1038/s41388-021-02076-x
Keywords
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Funding
- University of Utah Flow Cytometry Facility
- American Cancer Society [RSG CSM130435]
- V Scholar Award
- Burroughs Wellcome Fund
- American Lung Association Research Grant
- [K01CA168850]
- [R21CA215891]
- [5P30CA042014-24]
- [1S10RR026802-01]
- [R01CA212415]
- [R01CA240317]
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NKX2-1 suppresses ERK activity by inducing the ERK phosphatase DUSP6, inhibiting tumor growth and metastasis in lung adenocarcinoma.
The RAS -> RAF -> MEK -> ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.
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