Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
- University of Florida, United States
- Sun Yat-sen University, China
- Zhejiang University, China
- NIH, United States
- University of Florida College of Medicine, United States
Abstract
Lung cancer with loss-of-function of the LKB1 tumor suppressor is a common aggressive subgroup with no effective therapies. LKB1-deficiency induces constitutive activation of cAMP/CREB-mediated transcription by a family of three CREB-regulated transcription coactivators (CRTC1-3). However, the significance and mechanism of CRTC activation in promoting the aggressive phenotype of LKB1-null cancer remain poorly characterized. Here we observed overlapping CRTC expression patterns and mild growth phenotypes of individual CRTC-knockouts in lung cancer, suggesting functional redundancy of CRTC1-3. We consequently designed a dominant-negative mutant (dnCRTC) to block all three CRTCs to bind and co-activate CREB. Expression of dnCRTC efficiently inhibited the aberrantly activated cAMP/CREB-mediated oncogenic transcriptional program induced by LKB1-deficiency, and specifically blocked the growth of human and murine LKB1-inactivated lung cancer. Collectively, this study provides direct proof for an essential role of the CRTC-CREB activation in promoting the malignant phenotypes of LKB1-null lung cancer and proposes the CRTC-CREB interaction interface as a novel therapeutic target.
Data availability
The transcriptomic data were deposited in the NCBI GEO database GSE157722.All data generated or analyzed for this study are included in the manuscript.
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Identification of the dnCRTC-regulated genes in lung cancer cellsNCBI Gene Expression Omnibus, GSE157722.
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Genome wide screen of CREB and CRTC2 occupancy in LKB1 mutant NSCLC cell line A549NCBI Gene Expression Omnibus, GSE128871.
Article and author information
Author details
Funding
National Cancer Institute (R01CA234351)
- Lizi Wu
National Institute of Dental and Craniofacial Research (R01DE023641)
- Lizi Wu
UF Health Cancer Center
- Lizi Wu
National Institute of Environmental Health Sciences (Z1AES103311-01)
- Franco J DeMayo
University of Florida Gatorade Trust
- Frederic J Kaye
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Animal studies were performed following a protocol approved by the IACUC (Institutional Animal Care & Use Committee) of the University of Florida (201810386). All animals were housed, cared for, and used in an animal care facility at the University of Florida that is fully accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care International (AAALAC) program in compliance with the Guide for the Care and Use of Laboratory Animals, the Animal Welfare Act and other applicable state and local regulations.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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