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 SekineHozumi Motohashi

研究成果: Article査読

9 被引用数 (Scopus)

抄録

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.

本文言語English
論文番号5911
ジャーナルNature communications
11
1
DOI
出版ステータスPublished - 2020 12

ASJC Scopus subject areas

  • 化学 (全般)
  • 生化学、遺伝学、分子生物学(全般)
  • 物理学および天文学(全般)

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