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Cancer Genes and Networks

Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells

Marjolaine Bauzone, Mouloud Souidi, Anne-Frédérique Dessein, Maxence Wisztorski, Audrey Vincent, Jean-Pascal Gimeno, Didier Monté, Isabelle Van Seuningen, Christian Gespach and Guillemette Huet
Marjolaine Bauzone
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
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Mouloud Souidi
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
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  • ORCID record for Mouloud Souidi
Anne-Frédérique Dessein
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
2Centre de Biopathologie, Lille CHU, Lille, France.
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Maxence Wisztorski
3Université Lille, Inserm, CHU Lille, U1192 – Protéomique Réponse Inflammatoire Spectrométrie de Masse – PRISM, Lille, France.
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  • ORCID record for Maxence Wisztorski
Audrey Vincent
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
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Jean-Pascal Gimeno
3Université Lille, Inserm, CHU Lille, U1192 – Protéomique Réponse Inflammatoire Spectrométrie de Masse – PRISM, Lille, France.
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Didier Monté
4CNRS ERL9002 Integrative Structural Biology, Lille, France.
5Université Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE – Risk Factors and Molecular Determinants of Aging-Related Diseases, Lille, France.
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  • ORCID record for Didier Monté
Isabelle Van Seuningen
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
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Christian Gespach
6Sorbonne Université, Inserm U938, Team TGFβ Signaling in Cellular Plasticity and Cancer, Centre de Recherche Saint-Antoine, CRSA, Paris, France.
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Guillemette Huet
1Université Lille, CNRS, Inserm, CHU Lille, UMR9020–UMR1277 – CANTHER – Cancer Heterogeneity, Plasticity and Resistance to Therapies, Lille, France.
2Centre de Biopathologie, Lille CHU, Lille, France.
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  • For correspondence: guillemette.huet@inserm.fr
DOI: 10.1158/1541-7786.MCR-20-0462
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Abstract

The mechanisms whereby the Hippo pathway effector YAP regulates cancer cell stemness, plasticity, and chemoresistance are not fully understood. We previously showed that in 5-fluorouracil (5-FU)–resistant colorectal cancer cells, the transcriptional coactivator YAP is differentially regulated at critical transitions connected with reversible quiescence/dormancy to promote metastasis. Here, we found that experimental YAP activation in 5-FU–sensitive and 5-FU–resistant HT29 colorectal cancer cells enhanced nuclear YAP localization and the transcript levels of the retinoic acid (RA) receptors RARα/γ and RAR target genes CYP26A1, ALDH1A3, and LGR5 through RA Response Elements (RARE). In these two cell models, constitutive YAP activation reinforced the expression of the stemness biomarkers and regulators ALDH1A3, LGR5, and OCT4. Conversely, YAP silencing, RAR/RXR inhibition by the pan-RAR antagonist BMS493, and vitamin A depletion downregulated stemness traits and self-renewal. Regarding the mechanisms engaged, proximity-dependent labeling, nuclear YAP pulldown coupled with mass spectrometry, and chromatin immunoprecipitation (ChIP)/re-ChIP experiments revealed: (i) the nuclear colocalization/interaction of YAP with RARγ and RXRs; and (ii) combined genomic co-occupancy of YAP, RARα/γ, and RXRα interactomes at proximal RAREs of LGR5 and ALDH1A3 promoters. Moreover, activation of the YAP/RAR-RXR cross-talk in colorectal cancer cells promoted RAR self-activation loops via vitamin A metabolism, RA, and active RAR ligands generated by ALDH1A3. Together, our data identify YAP as a bona fide RAR-RXR transcriptional coactivator that acts through RARE-activated stemness genes.

Implications: Targeting the newly identified YAP/RAR-RXR cross-talk implicated in cancer cell stemness maintenance may lead to multitarget combination therapies for patients with colorectal cancer.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;XX:XX–XX

  • Received May 19, 2020.
  • Revision received November 10, 2020.
  • Accepted January 12, 2021.
  • Published first January 20, 2021.
  • ©2021 American Association for Cancer Research.

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This OnlineFirst version was published on February 9, 2021
doi: 10.1158/1541-7786.MCR-20-0462

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Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells
Marjolaine Bauzone, Mouloud Souidi, Anne-Frédérique Dessein, Maxence Wisztorski, Audrey Vincent, Jean-Pascal Gimeno, Didier Monté, Isabelle Van Seuningen, Christian Gespach and Guillemette Huet
Mol Cancer Res February 9 2021 DOI: 10.1158/1541-7786.MCR-20-0462

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Cross-talk between YAP and RAR-RXR Drives Expression of Stemness Genes to Promote 5-FU Resistance and Self-Renewal in Colorectal Cancer Cells
Marjolaine Bauzone, Mouloud Souidi, Anne-Frédérique Dessein, Maxence Wisztorski, Audrey Vincent, Jean-Pascal Gimeno, Didier Monté, Isabelle Van Seuningen, Christian Gespach and Guillemette Huet
Mol Cancer Res February 9 2021 DOI: 10.1158/1541-7786.MCR-20-0462
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