Publication Date



Molecular Oncology


E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T-cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD-1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)-C and CR-B sites of the Pdcd1 promoter, namely mono-ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb-repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb-repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4-transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T-cell function and expands our understanding of the epigenetic control of Pdcd1 expression.


Animals, Mice, Programmed Cell Death 1 Receptor, Lysine, T-Lymphocytes, Polycomb-Group Proteins, Ligases, Polycomb Repressive Complex 1, Neoplasms, Mice, Knockout



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