TY - JOUR
T1 - Enhancer remodeling promotes tumor-initiating activity in NRF2-activated non-small cell lung cancers
AU - Okazaki, Keito
AU - Anzawa, Hayato
AU - Liu, Zun
AU - Ota, Nao
AU - Kitamura, Hiroshi
AU - Onodera, Yoshiaki
AU - Alam, Md Morshedul
AU - Matsumaru, Daisuke
AU - Suzuki, Takuma
AU - Katsuoka, Fumiki
AU - Tadaka, Shu
AU - Motoike, Ikuko
AU - Watanabe, Mika
AU - Hayasaka, Kazuki
AU - Sakurada, Akira
AU - Okada, Yoshinori
AU - Yamamoto, Masayuki
AU - Suzuki, Takashi
AU - Kinoshita, Kengo
AU - Sekine, Hiroki
AU - Motohashi, Hozumi
N1 - Funding Information:
We thank Dr. Christian Siebel for critical reading of the manuscript, Dr. Hideyuki Saya for advice on cancer stemness and Drs. Kazuhiko Igarashi, Hiroki Shima and Kyoko Ochiai for advice on NRF2 complex purification. We also thank Drs. Shota Endo and Toshiyuki Takai for document preparation for clinical studies, Ms. Nozomi Hatanaka for deep sequencing technical support, Ms. Eriko Naganuma for histological sample pre-paraiton and the Biomedical Research Core of the Tohoku University Graduate School of Medicine for their technical support. This work was supported by JSPS under grant numbers 18H02621 (H.M), 18H04794 (H.M.), 17F17116 (H.M.), 17K08618 (H.S.), and 16K12519 (K.K.), the Naito Foundation (H.M.), a research grant from the Princess Takamatsu Cancer Research Fund 15-24728 (H.M.), the Uehara Memorial Foundation (H.M.), a research grant from the Gonryo Medical Foundation (H.S.) and AMED under grant numbers JP18am0101067 (K.K.) and JP20gm5010002 (H.M.). The funders had no role in the study design, data collection and analysis, decision to publish or paper preparation.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-19593-0
DO - 10.1038/s41467-020-19593-0
M3 - Article
C2 - 33219226
AN - SCOPUS:85096324308
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5911
ER -
