Augmentation of Myc-Dependent Mitotic Gene Expression by the Pygopus2 Chromatin Effector

Abstract

Summary: Mitotic segregation of chromosomes requires precise coordination of many factors, yet evidence is lacking as to how genes encoding these elements are transcriptionally controlled. Here, we found that the Pygopus (Pygo)2 chromatin effector is indispensable for expression of the MYC-dependent genes that regulate cancer cell division. Depletion of Pygo2 arrested SKOV-3 cells at metaphase, which resulted from the failure of chromosomes to capture spindle microtubules, a critical step for chromosomal biorientation and segregation. This observation was consistent with global chromatin association findings in HeLa S3 cells, revealing the enrichment of Pygo2 and MYC at promoters of biorientation and segmentation genes, at which Pygo2 maintained histone H3K27 acetylation. Immunoprecipitation and proximity ligation assays demonstrated MYC and Pygo2 interacting in nuclei, corroborated in a heterologous MYC-driven prostate cancer model that was distinct from Wnt/β-catenin signaling. Our evidence supports a role for Pygo2 as an essential component of MYC oncogenic activity required for mitosis. : Pygo2 is emerging as a key chromatin effector in a variety of human cancers. Distinct from its role in the active Wnt/β-catenin transcriptional complex, Andrews et al. identify Pygo2 as a critical component of oncogenic MYC transcriptional complexes that control mitotic gene expression. Keywords: myc, Wnt, Pygopus, mitosis, oncogene, prostate cancer