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

Saxena, Meera and Kalathur, Ravi K. R. and Rubinstein, Natalia and Vettiger, Andrea and Sugiyama, Nami and Neutzner, Melanie and Coto-Llerena, Mairene and Kancherla, Venkatesh and Ercan, Caner and Piscuoglio, Salvatore and Fischer, Jonas and Fagiani, Ernesta and Cantù, Claudio and Basler, Konrad and Christofori, Gerhard. (2020) A Pygopus 2-Histone Interaction Is Critical for Cancer Cell Dedifferentiation and Progression in Malignant Breast Cancer. Cancer Research, 80 (17). pp. 3631-3648.

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Official URL: https://edoc.unibas.ch/78988/

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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 (H3K4me; 2/3; ) and participate in chromatin reading and writing. It remains unknown whether the Pygo2-H3K4me; 2/3; 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 H3K4me; 2/3; 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-H3K4me; 2/3; 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
UniBasel Contributors:Ercan, Caner
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Association for Cancer Research
ISSN:0008-5472
e-ISSN:1538-7445
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:29 Dec 2020 14:31
Deposited On:29 Dec 2020 14:31

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