@article{fceb1efa1f0349818d060880d53ae3b1,
title = "NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor",
abstract = "Constitutive nuclear factor κB (NF-κB) activation is a hallmark of colon tumor growth. Cyclin-dependent kinases (CDKs) are critical cell-cycle regulators, and inhibition of CDK activity has been used successfully as anticancer therapy. Here, we show that the NFE2L3 transcription factor functions as a key regulator in a pathway that links NF-κB signaling to the control of CDK1 activity, thereby driving colon cancer cell proliferation. We found that NFE2L3 expression is regulated by the RELA subunit of NF-κB and that NFE2L3 levels are elevated in patients with colon adenocarcinoma when compared with normal adjacent tissue. Silencing of NFE2L3 significantly decreases colon cancer cell proliferation in vitro and tumor growth in vivo. NFE2L3 knockdown results in increased levels of double homeobox factor 4 (DUX4), which functions as a direct inhibitor of CDK1. The discovered oncogenic pathway governing cell-cycle progression may open up unique avenues for precision cancer therapy.",
keywords = "NFE2L3, NF-κB, DUX4, CDK1, Cell cycle, colorectal cancer, CDK inhibitor, cell cycle",
author = "Marina Bury and {Le Calve}, Benjamin and Fr{\'e}d{\'e}ric Lessard and {Dal Maso}, Thomas and James Saliba and Carine Michiels and Gerardo Febeyre and Blank Vloker",
note = "Funding Information: We would like to thank Joo Yeoun Park, Isadore Dodard-Freedman, Meenakshi Kannan, Yusra Kassim, St{\'e}phane Richard, Koren Mann, Eric Milot, Colin Crist, Johan Wouters, Guido Bommer, and Alain Isra{\"e}l for reading of the manuscript and/or valuable discussions and/or material support. We would like to thank Alan Spatz and Leon van Kempen (JGH, Montreal) for human colon cancer samples and Jose Torres for analysis of pathology specimens. We would like to acknowledge the LDI Flow Cytometry Facility (LDI, Montreal) for their flow cytometry technical expertise and the ENCODE project consortium and the ENCODE production laboratory for generating the dataset. Bioinformatics analyses were performed at the Bioinformatics Core Facility at the Institute for Research in Immunology and Cancer (IRIC), Universit{\'e} de Montr{\'e}al (Montreal, QC, Canada). Proteomics analyses were performed by the Center for Advanced Proteomics Analyses (IRIC), a Node of the Canadian Genomic Innovation Network that is supported by the Canadian Government through Genome Canada. We also would like to thank L{\'e}opold Thabault and Rapha{\"e}l Fr{\'e}d{\'e}rick for access to the microscale thermophoresis platform (UCLouvain, Brussels) and Jocelyn Eidahl (Nationwide Children{\textquoteright}s Hospital, USA) and Fr{\'e}d{\'e}rique Copp{\'e}e (UMons, Mons) for the DUX4-GST plasmid. M.B. was supported by fellowships from McGill Integrated Cancer Research Training Program (MICRTP, Canada), Le Fonds de recherche du Qu{\'e}bec - Sant{\'e} (FRQS, Canada), and the Cole Foundation (Canada) ; B.L.C. was supported by T{\'e}l{\'e}vie fellowship ( FNRS , Belgium); F.L. was supported by FRQS and CRS (Cancer Research Society, Canada) postdoctoral fellowships; T.D.M was supported by Fund for Research training in Industry and Agriculture ( FRIA , Belgium); and J.S. was supported by SEG (Lebanon) and MICRTP studentships. The research was supported by grants from the Canadian Institutes of Health Research (CIHR, Canada) MOP-97932 and PJT-152937 to V.B. Funding Information: We would like to thank Joo Yeoun Park, Isadore Dodard-Freedman, Meenakshi Kannan, Yusra Kassim, St?phane Richard, Koren Mann, Eric Milot, Colin Crist, Johan Wouters, Guido Bommer, and Alain Isra?l for reading of the manuscript and/or valuable discussions and/or material support. We would like to thank Alan Spatz and Leon van Kempen (JGH, Montreal) for human colon cancer samples and Jose Torres for analysis of pathology specimens. We would like to acknowledge the LDI Flow Cytometry Facility (LDI, Montreal) for their flow cytometry technical expertise and the ENCODE project consortium and the ENCODE production laboratory for generating the dataset. Bioinformatics analyses were performed at the Bioinformatics Core Facility at the Institute for Research in Immunology and Cancer (IRIC), Universit? de Montr?al (Montreal, QC, Canada). Proteomics analyses were performed by the Center for Advanced Proteomics Analyses (IRIC), a Node of the Canadian Genomic Innovation Network that is supported by the Canadian Government through Genome Canada. We also would like to thank L?opold Thabault and Rapha?l Fr?d?rick for access to the microscale thermophoresis platform (UCLouvain, Brussels) and Jocelyn Eidahl (Nationwide Children's Hospital, USA) and Fr?d?rique Copp?e (UMons, Mons) for the DUX4-GST plasmid. M.B. was supported by fellowships from McGill Integrated Cancer Research Training Program (MICRTP, Canada), Le Fonds de recherche du Qu?bec - Sant? (FRQS, Canada), and the Cole Foundation (Canada); B.L.C. was supported by T?l?vie fellowship (FNRS, Belgium); F.L. was supported by FRQS and CRS (Cancer Research Society, Canada) postdoctoral fellowships; T.D.M was supported by Fund for Research training in Industry and Agriculture (FRIA, Belgium); and J.S. was supported by SEG (Lebanon) and MICRTP studentships. The research was supported by grants from the Canadian Institutes of Health Research (CIHR, Canada) MOP-97932 and PJT-152937 to V.B. Conceptualization, M.B. B.L.C. and V.B.; Methodology, M.B. and B.L.C.; Investigation and Validation, M.B. B.L.C. F.L. T.D.M. and J.S.; Resources, C.M. G.F. and V.B.; Writing ? Original Draft, M.B. B.L.C. and V.B.; Writing ? Review & Editing, M.B. B.L.C. and V.B.; Visualization, M.B.; Supervision, C.M. G.F. and V.B.; Funding Acquisition, V.B. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2019 The Authors Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = nov,
day = "5",
doi = "10.1016/j.celrep.2019.09.087",
language = "English",
volume = "29",
pages = "1469--1481.e9",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "6",
}
