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Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma

Oncogene (2018) | Download Citation

Abstract

It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits. We demonstrate that PAX6 acts as an oncogene responsible for induction of cancer stemness properties in lung adenocarcinoma (LUAD). Mechanistically, PAX6 promotes GLI transcription, resulting in SOX2 upregulation directly by the binding of GLI to the proximal promoter region of the SOX2 gene. The overexpressed SOX2 enhances the expression of key pluripotent factors (OCT4 and NANOG) and suppresses differentiation lineage factors (HOPX and NKX2-1), driving cancer cells toward a stem-like state. In contrast, in the differentiated non-CSCs, PAX6 is transcriptionally silenced by its promoter methylation. In human lung cancer tissues, the positive linear correlations of PAX6 expression with GLI and SOX2 expression and its negative correlations with HOPX and NKX2-1 expression were observed. Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy. Furthermore, a methylation panel including the PAX6 gene yielded a sensitivity of 79.1% and specificity of 83.3% for cancer detection using serum DNA from stage IA LUAD. Our findings provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis with chemotherapy as an effective therapeutic strategy and support the clinical utility of PAX6 gene promoter methylation as a biomarker for early lung cancer detection.

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Funding

This work was funded by the Flight Attendant Medical Research Institute Clinical Innovative Award 103015 (M.O. Hoque), NCI R01CA206027 (M.O. Hoque), the Career Development award from SPORE in Cervical Cancer Grants P50 CA098252 (MOH).

Author information

Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    • Akira Ooki
    •  & Mohammad O. Hoque
  2. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA

    • Wikum Dinalankara
    • , Luigi Marchionni
    •  & Mohammad O. Hoque
  3. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, New York University School of Medicine, New York, NY, 10016, USA

    • Jun-Chieh J. Tsay
    •  & William N. Rom
  4. Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University of Medicine, New York, NY, 10016, USA

    • Chandra Goparaju
    •  & Harvey I. Pass
  5. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    • Zahra Maleki
  6. Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA

    • Mohammad O. Hoque

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The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Mohammad O. Hoque.

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DOI

https://doi.org/10.1038/s41388-018-0373-2