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

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.

Metrics

  • 1,732
    Page views
  • 255
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: PubMed Central, Crossref, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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
(2021)
Dependency of human and murine LKB1-inactivated lung cancer on aberrant CRTC-CREB activation
eLife 10:e66095.
https://doi.org/10.7554/eLife.66095
  1. Further reading

Further reading

    1. Cancer Biology
    2. Medicine
    Huan-Huan Chen, Tie-Ning Zhang ... Tao Zhang
    Research Article Updated

    Background:

    Sarcomas comprise approximately 1% of all human malignancies; treatment resistance is one of the major reasons for the poor prognosis of sarcomas. Accumulating evidence suggests that non-coding RNAs (ncRNAs), including miRNAs, long ncRNAs, and circular RNAs, are important molecules involved in the crosstalk between resistance to chemotherapy, targeted therapy, and radiotherapy via various pathways.

    Methods:

    We searched the PubMed (MEDLINE) database for articles regarding sarcoma-associated ncRNAs from inception to August 17, 2022. Studies investigating the roles of host-derived miRNAs, long ncRNAs, and circular RNAs in sarcoma were included. Data relating to the roles of ncRNAs in therapeutic regulation and their applicability as biomarkers for predicting the therapeutic response of sarcomas were extracted. Two independent researchers assessed the quality of the studies using the Würzburg Methodological Quality Score (W-MeQS).

    Results:

    Observational studies revealed the ectopic expression of ncRNAs in sarcoma patients who had different responses to antitumor treatments. Experimental studies have confirmed crosstalk between cellular pathways pertinent to chemotherapy, targeted therapy, and radiotherapy resistance. Of the included studies, W-MeQS scores ranged from 3 to 10 (average score = 5.42). Of the 12 articles that investigated ncRNAs as biomarkers, none included a validation cohort. Selective reporting of the sensitivity, specificity, and receiver operating curves was common.

    Conclusions:

    Although ncRNAs appear to be good candidates as biomarkers for predicting treatment response and therapeutics for sarcoma, their differential expression across tissues complicates their application. Further research regarding their potential for inhibiting or activating these regulatory molecules to reverse treatment resistance may be useful.

    Funding:

    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).

    1. Cancer Biology
    James Boot, Gabriel Rosser ... Silvia Marino
    Research Article

    We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.