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Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers

Author

Listed:
  • Keito Okazaki

    (Tohoku University)

  • Hayato Anzawa

    (Tohoku University)

  • Zun Liu

    (Tohoku University)

  • Nao Ota

    (Tohoku University)

  • Hiroshi Kitamura

    (Tohoku University)

  • Yoshiaki Onodera

    (Tohoku University Graduate School of Medicine)

  • Md. Morshedul Alam

    (Tohoku University)

  • Daisuke Matsumaru

    (Tohoku University)

  • Takuma Suzuki

    (Tohoku University)

  • Fumiki Katsuoka

    (Tohoku University)

  • Shu Tadaka

    (Tohoku University)

  • Ikuko Motoike

    (Tohoku University)

  • Mika Watanabe

    (Tohoku University Hospital)

  • Kazuki Hayasaka

    (Tohoku University
    Tohoku University)

  • Akira Sakurada

    (Tohoku University)

  • Yoshinori Okada

    (Tohoku University)

  • Masayuki Yamamoto

    (Tohoku University
    Tohoku University Graduate School of Medicine)

  • Takashi Suzuki

    (Tohoku University Graduate School of Medicine)

  • Kengo Kinoshita

    (Tohoku University
    Tohoku University)

  • Hiroki Sekine

    (Tohoku University)

  • Hozumi Motohashi

    (Tohoku University)

Abstract

Transcriptional dysregulation, which can be caused by genetic and epigenetic alterations, is a fundamental feature of many cancers. A key cytoprotective transcriptional activator, NRF2, is often aberrantly activated in non-small cell lung cancers (NSCLCs) and supports both aggressive tumorigenesis and therapeutic resistance. Herein, we find that persistently activated NRF2 in NSCLCs generates enhancers at gene loci that are not normally regulated by transiently activated NRF2 under physiological conditions. Elevated accumulation of CEBPB in NRF2-activated NSCLCs is found to be one of the prerequisites for establishment of the unique NRF2-dependent enhancers, among which the NOTCH3 enhancer is shown to be critical for promotion of tumor-initiating activity. Enhancer remodeling mediated by NRF2-CEBPB cooperativity promotes tumor-initiating activity and drives malignancy of NRF2-activated NSCLCs via establishment of the NRF2-NOTCH3 regulatory axis.

Suggested Citation

  • Keito Okazaki & Hayato Anzawa & Zun Liu & Nao Ota & Hiroshi Kitamura & Yoshiaki Onodera & Md. Morshedul Alam & Daisuke Matsumaru & Takuma Suzuki & Fumiki Katsuoka & Shu Tadaka & Ikuko Motoike & Mika W, 2020. "Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19593-0
    DOI: 10.1038/s41467-020-19593-0
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