Department of Biomedicine, University of Basel, Basel, Switzerland.
Institute of Pathology, University Hospital Basel, Basel, Switzerland.
Cancer Res. 2020 Sep 1;80(17):3631-3648. doi: 10.1158/0008-5472.CAN-19-2910. Epub 2020 Jun 25.
Pygopus 2 (Pygo2) is a coactivator of Wnt/β-catenin signaling that can bind bi- or trimethylated lysine 4 of histone-3 (H3K4me) and participate in chromatin reading and writing. It remains unknown whether the Pygo2-H3K4me association has a functional relevance in breast cancer progression . 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 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 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.
Pygo2（Pygo2）是 Wnt/β-catenin 信号通路的共激活因子，能够结合组蛋白-3（H3K4me）的双或三甲基化赖氨酸 4，并参与染色质的读取和书写。目前尚不清楚 Pygo2-H3K4me 结合是否与乳腺癌的进展具有功能相关性。为了研究 Pygo2 与 H3K4me 结合在乳腺癌恶性进展中的功能相关性，我们生成了一种敲入小鼠模型，其中 Pygo2 与 H3K4me 的结合变得无效。由于经典 Wnt/β-catenin 信号的降低，Pygo2-组蛋白相互作用的丧失导致肿瘤体积更小、分化程度更高、转移能力更低。肿瘤衍生细胞系的 RNA 和 ATAC 测序分析表明，TGFβ 信号通路下调，分化途径如 PDGFR 信号通路上调。分化增加与腔细胞命运相关，PDGFR 活性的抑制可逆转这种命运。从机制上讲，Pygo2-组蛋白相互作用通过抑制 Wnt 信号通路拮抗剂的表达来增强 Wnt/β-catenin 信号通路。此外，Pygo2 和 β-catenin 调节 miR-29 家族成员的表达，而 miR-29 家族成员反过来又抑制 PDGFR 的表达，从而促进野生型 Pygo2 乳腺上皮肿瘤细胞的去分化。总的来说，这些结果表明，Pygo2 的组蛋白结合功能对于驱动乳腺癌的去分化和恶性转化非常重要，而这种结合的丧失激活了各种分化途径，从而减弱了原发性肿瘤的生长和转移形成。因此，干扰 Pygo2-H3K4me 相互作用可能成为转移性乳腺癌的一种有吸引力的治疗靶点。
Pygo2 是转移性乳腺癌的一个潜在治疗靶点，因为其组蛋白结合能力促进了乳腺癌细胞去分化、EMT 和转移过程中β-catenin 介导的 Wnt 信号和转录调控。
