1. Cancer Biology
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Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation

  1. Xin Zhou
  2. Jennifer W Li
  3. Zirong Chen
  4. Wei Ni
  5. Xuehui Li
  6. Rongqiang Yang
  7. Huangxuan Shen
  8. Jian Liu
  9. Franco J DeMayo
  10. Jianrong Lu
  11. Frederic J Kaye
  12. Lizi Wu  Is a corresponding author
  1. University of Florida, United States
  2. Sun Yat-sen University, China
  3. Zhejiang University, China
  4. NIH, United States
  5. University of Florida College of Medicine, United States
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Cite this article as: eLife 2021;10:e66095 doi: 10.7554/eLife.66095

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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Xin Zhou

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Jennifer W Li

    Department of Medicine, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Zirong Chen

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Wei Ni

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Xuehui Li

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Rongqiang Yang

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Huangxuan Shen

    Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
    Competing interests
    The authors declare that no competing interests exist.

  8. Jian Liu

    ZJU-UoE Institute, Zhejiang University, Haining, China
    Competing interests
    The authors declare that no competing interests exist.

  9. Franco J DeMayo

    NIH, Research Triangle Park, United States
    Competing interests
    The authors declare that no competing interests exist.

  10. Jianrong Lu

    Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4969-6040

  11. Frederic J Kaye

    Medicine, University of Florida, Gainesville, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Lizi Wu

    Molecular Genetics & Microbiology, University of Florida, Gainesville, United States
    For correspondence
    lzwu@ufl.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0076-2617

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.

Reviewing Editor

  1. Erica A Golemis, Fox Chase Cancer Center, United States

Publication history

  1. Received: December 29, 2020
  2. Accepted: June 17, 2021
  3. Accepted Manuscript published: June 18, 2021 (version 1)
  4. Version of Record published: June 28, 2021 (version 2)
  5. Version of Record updated: July 2, 2021 (version 3)

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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