Pygo2 activates BRPF1 via Pygo2-H3K4me2/3 interaction to maintain malignant progression in colon cancer

Epigenetic alterations have essential roles during colon adenocarcinoma (COAD) progression. As the coactivator of Wnt/b-catenin signaling, Pygopus 2 (Pygo2) binds H3K4me2/3 and participate in chromatin remodeling in multiple cancers. However, It remains unclear whether the Pygo2-H3K4me2/3 association has significance in COAD. We aimed to elucidate the roles of Pygo2 in COAD. Functionally, Pygo2 inhibition attenuated cell proliferation, self-renewal capacities in vitro. Pygo2 overexpression enhanced in vivo tumor growth. Besides, Pygo2 overexpression could also enhance cell migration ability and in vivo distal metastasis. Mechanistically, Pygo2 correlates positively with BRPF1 expressions, one epigenetic reader of histone acetylation. The luciferase reporter assay and Chromatin Immunoprecipitation (ChIP)-qPCR assay were used to find that Pygo2 coordinated with H3K4me2/3 modifications to activate BRPF1 transcriptions via binding to the promoter. Both Pygo2 and BRPF1 expressed highly in tumors and Pygo2 relied on BRPF1 to accelerate COAD progression, including cell proliferation rate, migration abilities, stemness features and in vivo tumor growth. Targeting BPRF1 (GSK5959) is effective to suppress in vitro growth of Pygo2^high cell lines, and has mild effect on Pygo2^low cells. The subcutaneous tumor model further demonstrated that GSK5959 could effectively suppress the in vivo growth of Pygo2^high COAD, but not the Pygo2^low subtype. Collectively, our study represented Pygo2/BRPF1 as an epigenetic vulnerability for COAD treatment with predictive significance.