Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin, China.
Department of Biochemistry and Molecular Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
J Cell Physiol. 2023 Nov;238(11):2710-2723. doi: 10.1002/jcp.31124. Epub 2023 Sep 21.
Dysregulation of polycomb group (PcG) proteins that mediate epigenetic gene silencing contributes to tumorigenesis. As core components of the polycomb repressive complex 1 (PRC1), chromobox (CBX) proteins recognize H3K27me3 to recruit PRC1 to maintain a repressive transcriptional state. However, the individual biological functions of these CBX proteins in tumorigenesis warrant in-depth investigation. In this study, we analyzed the mRNA expression of CBX family genes across multiple cancers using The Cancer Genome Atlas data and found different expression patterns of the five CBX genes in different types of cancer. This analyses together with the result of immunohistochemistry indicated that CBX8 expression was significantly higher in lung adenocarcinoma (LUAD) tissues compared to adjacent nontumor tissues. Overexpression approaches demonstrated that CBX8 facilitated LUAD cell proliferation and migration in vitro. Consistently, CBX8 knockdown reduced LUAD cell proliferation and migration in both cell culture and mouse models. RNA sequencing combined with real-time RT-PCR assays revealed CDKN2C and SCEL as target genes of CBX8. Furthermore, chromatin immunoprecipitation assays indicated that CBX8 directly bound to the promoters of CDKN2C and SCEL to establish H2AK119ub. CBX8 depletion reduced the enrichment of H2AK119ub on CDKN2C and SCEL promoters. Moreover, depletion of CDKN2C and SCEL restored the repressed growth and invasion ability of LUAD cells caused by CBX8 knockdown. These findings demonstrate that CBX8 promotes LUAD growth and metastasis through the transcriptional repression of CDKN2C and SCEL. Our study uncovers the oncogenic role of CBX8 in LUAD progression and provides a new target for the diagnosis and therapy of LUAD.
多梳抑制复合物（PcG）蛋白的失调介导表观遗传基因沉默，导致肿瘤发生。作为多梳抑制复合物 1（PRC1）的核心组成部分，染色盒（CBX）蛋白识别 H3K27me3 以募集 PRC1 来维持抑制性转录状态。然而，这些 CBX 蛋白在肿瘤发生中的个体生物学功能需要深入研究。在这项研究中，我们使用癌症基因组图谱（TCGA）数据分析了 CBX 家族基因在多种癌症中的 mRNA 表达，发现了不同类型癌症中五种 CBX 基因的不同表达模式。这些分析结果以及免疫组织化学的结果表明，CBX8 在肺腺癌（LUAD）组织中的表达明显高于相邻非肿瘤组织。过表达方法表明，CBX8 在体外促进 LUAD 细胞增殖和迁移。一致地，CBX8 敲低减少了在细胞培养和小鼠模型中 LUAD 细胞的增殖和迁移。RNA 测序结合实时 RT-PCR 分析显示 CDKN2C 和 SCEL 是 CBX8 的靶基因。此外，染色质免疫沉淀分析表明，CBX8 直接结合到 CDKN2C 和 SCEL 基因的启动子上，建立 H2AK119ub。CBX8 耗竭减少了 H2AK119ub 在 CDKN2C 和 SCEL 启动子上的富集。此外，CDKN2C 和 SCEL 的耗竭恢复了 CBX8 敲低导致的 LUAD 细胞生长和侵袭能力的抑制。这些发现表明，CBX8 通过转录抑制 CDKN2C 和 SCEL 促进 LUAD 的生长和转移。我们的研究揭示了 CBX8 在 LUAD 进展中的致癌作用，并为 LUAD 的诊断和治疗提供了新的靶点。
