NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

Marina Bury; Benjamin Le Calve; Frédéric Lessard; Thomas Dal Maso; James Saliba; Carine Michiels; Gerardo Febeyre; Blank Vloker

doi:10.1016/j.celrep.2019.09.087

NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

Marina Bury
, Benjamin Le Calve
, Frédéric Lessard
, Thomas Dal Maso
, James Saliba
, Carine Michiels
, Gerardo Febeyre
, Blank Vloker

Research output: Contribution to journal › Article › peer-review

104 Downloads (Pure)

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.

Original language	English
Pages (from-to)	1469-1481.e9
Journal	Cell Reports
Volume	29
Issue number	6
DOIs	https://doi.org/10.1016/j.celrep.2019.09.087
Publication status	Published - 5 Nov 2019

Funding

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. We would like to thank Joo Yeoun Park, Isadore Dodard-Freedman, Meenakshi Kannan, Yusra Kassim, Stéphane Richard, Koren Mann, Eric Milot, Colin Crist, Johan Wouters, Guido Bommer, and Alain Israël 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), Université de Montréal (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 Léopold Thabault and Raphaël Frédérick for access to the microscale thermophoresis platform (UCLouvain, Brussels) and Jocelyn Eidahl (Nationwide Children’s Hospital, USA) and Frédérique Coppée (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 Québec - Santé (FRQS, Canada), and the Cole Foundation (Canada) ; B.L.C. was supported by Télévie 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.

Funders	Funder number
Sociedad Española de Glaucoma
Genome Canada
Cancer Research Society
Télévie fellowship
Fonds de Recherche du Québec - Santé
Nationwide Children's Hospital
T?l?vie fellowship
McGill Integrated Cancer Research Training Program
Fr?d?rique Copp?e
Cole Foundation
Fonds De La Recherche Scientifique - FNRS
Jocelyn Eidahl
Alan Spatz and Leon van Kempen
Canadian Institutes of Health Research	MOP-97932, PJT-152937

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being
SDG 9 Industry, Innovation, and Infrastructure

Keywords

NFE2L3
NF-κB
DUX4
CDK1
Cell cycle
colorectal cancer
CDK inhibitor
cell cycle

Access to Document

10.1016/j.celrep.2019.09.087

mmc3Final published version, 5.37 MBLicence: CC BY-NC-ND

Cite this

@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 = "Elsevier",

number = "6",

}

TY - JOUR

T1 - NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

AU - Bury, Marina

AU - Le Calve, Benjamin

AU - Lessard, Frédéric

AU - Dal Maso, Thomas

AU - Saliba, James

AU - Michiels, Carine

AU - Febeyre, Gerardo

AU - Vloker, Blank

N1 - Funding Information: We would like to thank Joo Yeoun Park, Isadore Dodard-Freedman, Meenakshi Kannan, Yusra Kassim, Stéphane Richard, Koren Mann, Eric Milot, Colin Crist, Johan Wouters, Guido Bommer, and Alain Israël 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), Université de Montréal (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 Léopold Thabault and Raphaël Frédérick for access to the microscale thermophoresis platform (UCLouvain, Brussels) and Jocelyn Eidahl (Nationwide Children’s Hospital, USA) and Frédérique Coppée (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 Québec - Santé (FRQS, Canada), and the Cole Foundation (Canada) ; B.L.C. was supported by Télévie 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: © 2019 The Authors Copyright: Copyright 2019 Elsevier B.V., All rights reserved.

PY - 2019/11/5

Y1 - 2019/11/5

N2 - 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.

AB - 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.

KW - NFE2L3

KW - NF-κB

KW - DUX4

KW - CDK1

KW - Cell cycle

KW - colorectal cancer

KW - CDK inhibitor

KW - cell cycle

UR - https://www.scopus.com/pages/publications/85074248772

U2 - 10.1016/j.celrep.2019.09.087

DO - 10.1016/j.celrep.2019.09.087

M3 - Article

SN - 2211-1247

VL - 29

SP - 1469-1481.e9

JO - Cell Reports

JF - Cell Reports

IS - 6

ER -

NFE2L3 Controls Colon Cancer Cell Growth through Regulation of DUX4, a CDK1 Inhibitor

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UN SDGs

Keywords

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