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

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A Pygopus 2-Histone Interaction Is Critical for Cancer Cell De-Differentiation and Progression in Malignant Breast Cancer Author Manuscript Published OnlineFirst on June 25, 2020; DOI: 10.1158/0008-5472.CAN-19-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Saxena et al. A Pygopus 2-histone interaction is critical for cancer cell de-differentiation and progression in malignant breast cancer Meera Saxena1,*, Ravi K.R. Kalathur1,4,#, Natalia Rubinstein1,5,#, Andrea Vettiger1,6, Nami Sugiyama1, Melanie Neutzner1, Mairene Coto-Llerena2, Venkatesh Kancherla2, Caner Erkan2, Salvatore Piscuoglio2, Jonas Fischer1, Ernesta Fagiani1, Claudio Cantù3,7, Konrad Basler3 and Gerhard Christofori1,* 1Department of Biomedicine, University of Basel, Switzerland 2Institute of Pathology, University Hospital Basel, Switzerland 3Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland Current affiliations: 4Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia 5Institute of Biosciences, Biotechnology and Translational Biology, Department of Physiology, Molecular and Cellular Biology, Faculty of Exact Science, University of Buenos Aires, Buenos Aires, Argentina 6Balvatnik Institute, Harvard Medical School, Boston, United States of America 7Wallenberg Centre for Molecular Medicine Linköping; Department of Biomedical and Clinical Sciences, Faculty of Health Science, Linköping University, Sweden #Authors contributed equally *Corresponding authors: Meera Saxena and Gerhard Christofori Department of Biomedicine, University of Basel Mattenstrasse 28, CH-4058 Basel, Switzerland Tel. +41 61 207 35 64 Fax. +41 61 207 35 66 E-mail: [email protected]; [email protected] Running Title: Pygo2 promotes breast cancer progression The authors declare no potential conflicts of interest. Word Count: 6640 words (main text); 7 Figures, 7 Supplementary Figures, 3 Supplementary Tables and 4 Supplementary Videos. 1 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 25, 2020; DOI: 10.1158/0008-5472.CAN-19-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Saxena et al. Abstract Pygopus 2 (Pygo2) is a co- -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, -catenin signaling. RNA and ATAC sequencing analyses of tumor-derived cell lines revealed downregulation signaling and upregulation of differentiation pathways such as PDGFR signaling. Increased differentiation correlated with a luminal cell fate which could be reversed by inhibition of PDGFR activity. Mechanistically, the Pygo2-histone interaction p -catenin signaling in part -catenin regulated the expression of miR-29 family members which in turn repressed PDGFR expression to promote de- differentiation of wildtype Pygo2 mammary epithelial tumor cells. Collectively, these results demonstrate that the histone binding function of Pygo2 is important for driving de- differentiation and malignancy of breast tumors, and loss of this binding activates various differentiation pathways which 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 beta-catenin-mediated Wnt signaling and transcriptional control in breast cancer cell de-differentiation, EMT, and metastasis. Keywords Breast cancer, de-differentiation, Pygo2, Wnt/ -catenin, PDGFR Introduction Breast cancer is the most frequent malignancy in women worldwide. Localized, differentiated breast cancers, as represented by the luminal subtypes, are responsive to therapeutic intervention (1). However, de-differentiated, aggressive subtypes, characterized as basal-like/triple-negative, in most cases represent therapy refractory primary tumors concomitant with the formation of distant metastasis (1). Inappropriate activation of the Wnt signaling pathway, for example by activating mutations in positively acting components or loss of function of negative regulators of the pathway, 2 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 25, 2020; DOI: 10.1158/0008-5472.CAN-19-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Saxena et al. has been shown to drive several malignancies including breast cancer (2). The transcriptional activity of -catenin, the key transcriptional effector of Wnt signaling, is aided by binding to the co- transcriptional activators Pygopus 1 and 2 (Pygo1 and 2) via the Bcl9/9L adaptor proteins (3,4). Pygo proteins were first discovered in Drosophila melanogaster (5-7) and in Xenopus (8). Of the two mammalian Pygo homologues, Pygo2 has been shown to be more abundantly expressed and functionally relevant than Pygo1 (9,10). While deletion of Pygo2 affects the proper development of multiple tissues, additional deletion of Pygo1 does not appear to exacerbate the Pygo2 phenotype (9- 12). Furthermore -catenin signaling has been found to be context- -catenin-independent manner in lens development (12,13), in tooth enamel formation (14) and in spermatogenesis (11). However, during the activation of hair follicle stem/progenitor cells and the regeneration of skin (15) and also during the development of mammary glands and expansion of mammary stem/progenitor cells, Pygo2 functions at least in part by regulating Wnt/ -catenin signaling (16). The best-characterized function of the Pygo proteins is in cell proliferation. At actively transcribing gene loci, Pygo2 binds activating histone marks, such as bi- or trimethylated histones (H3K4me2/3), and recruits histone acetyltransferases (HAT) which in turn promote an open chromatin structure (17-19). Moreover, by acting as an epigenetic accessory protein, Pygo2 drives Myc- dependent activation of mitosis-related genes (20). Befitting its role in proliferation, an increased expression of Pygo2 has been observed in several malignancies, including ovarian cancer (21), glioma (22), lung cancer (23), hepatocellular carcinoma (24), and prostate cancer (25). Importantly, Pygo2 upregulation has also been observed in breast cancer (18,26). Interestingly, Pygo2 resides in the chromosomal region 1q21-q22, which is found to be amplified in more than half of breast cancer cases (27). In the breast, Pygo2 plays an important role in mammary lineage differentiation. Pygo2 maintains the fate of mammary stem cells/basal cells by suppressing their luminal/alveolar differentiation, at least in part through the suppression of Notch signaling (28). Finally, ablation of Pygo2 in the mammary gland was found to delay the onset of tumors in the Wnt signaling-driven MMTV-Wnt1 transgenic mouse model of breast cancer (29). The Pygo family proteins contain a highly conserved C-terminal plant homology domain (PHD) which mediates the direct binding to H3K4me2/3, a mark of active transcription (16,19,30). PHD- thus linking chromatin remodeling to changes in gene transcription (31) by interacting with and recruiting histone acetyltransferases (HAT), such as CBP [CREB (cAMP- responsive-element-binding protein)-binding protein] (17), or histone methyl transferases (HMT), such as mixed lineage leukemia-2 (MLL2) (18), and thus augments -catenin-mediated 3 Downloaded from cancerres.aacrjournals.org on October 4, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 25, 2020; DOI: 10.1158/0008-5472.CAN-19-2910 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Saxena et al. transcriptional activation. Hence, Pygo2 can function as an efficient chromatin effector participating (11,16). However, whether, the Pygo2-H3K4me2/3 association has a functional relevance in breast cancer progression in vivo has remained elusive. Here, we report that the interaction of Pygo2 with histones is critical for -catenin-driven de-differentiated invasive breast cancer and metastasis formation. In mammary tumors of knock-in mice carrying Pygo2 alleles which are unable to bind to H3K4me2/3, differentiation inducing pathways like PDGFR get activated and promote a luminal cell fate, thereby repressing primary tumor invasiveness and metastasis formation. Materials and Methods Antibodies and reagents Axin-2 (Abcam, ab32197), -tubulin (Sigma, T-9026), -catenin (BD transduction labs, 610154; used for immunofluorescence staining of tumor spheroids), -catenin (Novus Biologicals, NBP1-32239; used for ChIP experiments), non-phospho (active) -catenin (Ser33/37/Thr41) (D13A1) (Cell signaling technology, 8814; used for immunoblotting), cleaved Caspase-3 (Cell Signaling Technology, 9664), c-Myc (D84C12) (Cell signaling technology, 5605), cyclin-D1 (EPR2241) (Abcam, ab134175), Cytokeratin-14 (ThermoFisher Scientific, RB-9020-P0),
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