Pygopus 2-histone interaction is critical for cancer cell de-differentiation and malignant breast cancer progression

MEERA SAXENA; NATALIA RUBINSTEIN.; RAVI K. KALATHUR ; ANDREA VETTIGER; NAMI SUGIYAMA; MELANIE NEUTZNER; MAIRENE COTO-LLERENA; VENKATESH KANCHERLA; CANER ERCAN; SALVATORE PISCUOGLIO; JONAS FISCHER; ERNESTA FAGIANI ; CLAUDIO CANTÙ; KONRAD BASLER; GERHARD CHRISTOFORI

CANCER RESEARCH

AMER ASSOC CANCER RESEARCH

Lugar: Philadelphia; Año: 2020

0008-5472

Pygopus 2 (Pygo2), a co-activator of Wnt/-catenin signaling, can also bind bi- or trimethylated lysine 4 of histone-3 (H3K4me2/3) and participate in chromatin reading and writing. However, whether the Pygo2-H3K4me2/3 association has a functional relevance in breast cancer progression in vivo, has remained elusive. To investigate the functional relevance of histone binding activity of Pygo2 in malignant progression of breast cancer, we generated a knock-in mouse model wherein binding of Pygo2 to H3K4me2/3 was rendered ineffective. Loss of Pygo2-histone binding resulted in smaller, differentiated and less metastatic tumors, at least in part due to decreased canonical Wnt/-catenin signaling. RNA and ATAC sequencing analyses of tumor-derived cell lines revealed a downregulation of TGF 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, we find that Pygo2-histone interaction potentiates Wnt/-catenin signaling, in part by repressing the expression of Wnt signaling antagonists. Further, Pygo2 and -catenin regulate the expression of miR-29 family members which in turn repress PDGFR expression, thereby promoting the de-differentiation of wildtype Pygo2 mammary epithelial tumor cells. Collectively, the results demonstrate that the histone-binding function of Pygo2 is important for driving de-differentiation and malignancy of breast tumors. Conversely, the loss of this binding activates various differentiation pathways which attenuate primary tumor growth and metastasis formation. Hence, interfering with the Pygo2-H3K4me2/3 interaction may serve as an attractive therapeutic target for metastatic breast cancer.