KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

T. Yu, X. Chen, W. Zhang, J. Liu, R. Avdiushko, D. L. Napier, A. X. Liu, J. M. Neltner, C. Wang, D. Cohen, C. Liu

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifen-induced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-rasLSL-G12D/+;Klf4fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

Original languageEnglish
Pages (from-to)207-215
Number of pages9
JournalCell Death and Differentiation
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2016

Bibliographical note

Funding Information:
Acknowledgements. We thank Garretson Epperly for technical support in image scan and analysis and the Markey Biospecimen and Tissue Procurement Shared Resource Facility for the tissue embedding, sectioning and H&E staining. And we thank Vivek M Rangnekar for the BEAS-2B cell line, and Vincent W Yang for the GKLF-pGL2-Luciferase reporter. The University of Kentucky Biospecimen and Tissue Procurement and Biostatistics and Bioinformatics Shared Resource Facilities are supported by the Markey Cancer Center (P30 CA177558). CL was supported by R01 CA172379 from the NIH.

Publisher Copyright:
© 2016 Macmillan Publishers Limited All rights reserved.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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