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

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 Watanabe, Kazuki Hayasaka, Akira Sakurada, Yoshinori Okada, Masayuki Yamamoto, Takashi Suzuki, Kengo Kinoshita, Hiroki Sekine () and Hozumi Motohashi ()
Additional contact information
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
Akira Sakurada: Tohoku University
Yoshinori Okada: Tohoku University
Masayuki Yamamoto: Tohoku University
Takashi Suzuki: Tohoku University Graduate School of Medicine
Kengo Kinoshita: Tohoku University
Hiroki Sekine: Tohoku University
Hozumi Motohashi: Tohoku University

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19593-0

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