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Tumor Biology and Immunology

A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer

Meera Saxena, Ravi K.R. Kalathur, Natalia Rubinstein, Andrea Vettiger, Nami Sugiyama, Melanie Neutzner, Mairene Coto-Llerena, Venkatesh Kancherla, Caner Ercan, Salvatore Piscuoglio, Jonas Fischer, Ernesta Fagiani, Claudio Cantù, Konrad Basler and Gerhard Christofori
Meera Saxena
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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  • For correspondence: gerhard.christofori@unibas.ch meera.saxena@unibas.ch
Ravi K.R. Kalathur
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Natalia Rubinstein
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Andrea Vettiger
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Nami Sugiyama
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Melanie Neutzner
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Mairene Coto-Llerena
2Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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Venkatesh Kancherla
2Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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Caner Ercan
2Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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Salvatore Piscuoglio
2Institute of Pathology, University Hospital Basel, Basel, Switzerland.
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Jonas Fischer
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Ernesta Fagiani
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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Claudio Cantù
3Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
4Wallenberg Centre for Molecular Medicine Linköping; Department of Biomedical and Clinical Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
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Konrad Basler
3Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
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Gerhard Christofori
1Department of Biomedicine, University of Basel, Basel, Switzerland.
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  • For correspondence: gerhard.christofori@unibas.ch meera.saxena@unibas.ch
DOI: 10.1158/0008-5472.CAN-19-2910 Published September 2020
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Abstract

Pygopus 2 (Pygo2) is a coactivator of Wnt/β-catenin signaling that can bind bi- or trimethylated lysine 4 of histone-3 (H3K4me2/3) and participate in chromatin reading and writing. It remains unknown whether the Pygo2–H3K4me2/3 association has a functional relevance in breast cancer progression in vivo. To investigate the functional relevance of histone-binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model where binding of Pygo2 to H3K4me2/3 was rendered ineffective. Loss of Pygo2–histone interaction resulted in smaller, differentiated, and less metastatic tumors, due, in part, to decreased canonical Wnt/β-catenin signaling. RNA- and ATAC-sequencing analyses of tumor-derived cell lines revealed downregulation of TGFβ signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate that could be reversed by inhibition of PDGFR activity. Mechanistically, the Pygo2–histone interaction potentiated Wnt/β-catenin signaling, in part, by repressing the expression of Wnt signaling antagonists. Furthermore, Pygo2 and β-catenin regulated the expression of miR-29 family members, which, in turn, repressed PDGFR expression to promote dedifferentiation of wild-type Pygo2 mammary epithelial tumor cells. Collectively, these results demonstrate that the histone binding function of Pygo2 is important for driving dedifferentiation and malignancy of breast tumors, and loss of this binding activates various differentiation pathways that attenuate primary tumor growth and metastasis formation. Interfering with the Pygo2–H3K4me2/3 interaction may therefore serve as an attractive therapeutic target for metastatic breast cancer.

Significance: Pygo2 represents a potential therapeutic target in metastatic breast cancer, as its histone-binding capability promotes β-catenin–mediated Wnt signaling and transcriptional control in breast cancer cell dedifferentiation, EMT, and metastasis.

Footnotes

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

  • Cancer Res 2020;80:3631–48

  • Received September 17, 2019.
  • Revision received April 19, 2020.
  • Accepted June 22, 2020.
  • Published first June 25, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (17)
September 2020
Volume 80, Issue 17
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A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer
Meera Saxena, Ravi K.R. Kalathur, Natalia Rubinstein, Andrea Vettiger, Nami Sugiyama, Melanie Neutzner, Mairene Coto-Llerena, Venkatesh Kancherla, Caner Ercan, Salvatore Piscuoglio, Jonas Fischer, Ernesta Fagiani, Claudio Cantù, Konrad Basler and Gerhard Christofori
Cancer Res September 1 2020 (80) (17) 3631-3648; DOI: 10.1158/0008-5472.CAN-19-2910

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A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer
Meera Saxena, Ravi K.R. Kalathur, Natalia Rubinstein, Andrea Vettiger, Nami Sugiyama, Melanie Neutzner, Mairene Coto-Llerena, Venkatesh Kancherla, Caner Ercan, Salvatore Piscuoglio, Jonas Fischer, Ernesta Fagiani, Claudio Cantù, Konrad Basler and Gerhard Christofori
Cancer Res September 1 2020 (80) (17) 3631-3648; DOI: 10.1158/0008-5472.CAN-19-2910
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