Abstract
Cancer cells exploit epigenetic modifications and post-transcriptional regulations to form oncogenic gene expression networks. However, how these machineries collaboratively orchestrate malignancy remains elusive. One of aberrant epigenetic pathways in cancer is Polycomb repressive complex 1 (PRC)-mediated H2AK119 monoubiquitination (H2AK119ub1) with subsequent silencing of tumor suppressor genes. Despite previous efforts, the biological and clinical significance of PRC1 remains unclear in neuroblastoma (NB), an aggressive sympathoadrenal solid tumor in children. In this study, we demonstrated that knockdown of RING1A, one of the E3 ubiquitin ligases of PRC1, reduced cell viability and enrichment of H2AK119ub1 in NB cells. Transcriptional profiling revealed RING1A-specific targets, whose lower expression was associated with poor outcomes in NB patients. Among these genes, BTG2, a component of the CCR4-NOT polyA deadenylase complex, harbored a hypomethylated CpG island occupied by H2AK119ub1 and accessory proteins of noncanonical PRC1.1 (ncPRC1.1). Biological experiments uncovered that BTG2 suppressed NB cell growth in vitro and inhibited tumor formation in vivo. Moreover, BTG2 perturbed cell cycle progression and selectively destabilized the mRNAs of the cyclin genes CCNA2, CCNB1, and CCNB2. In NB patient cohorts, lower expression of BTG2 was associated with poor outcomes and inversely correlated with those cyclin gene expression. Collectively, we have uncovered a crosstalk between epigenetic modifications and post-transcriptional regulations, in which ncPRC1.1-mediated silencing of BTG2 retains cyclin gene expression and cell proliferation in NB. This study provides new insights into how epigenetic pathways contribute to NB malignancy.