Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
Cell Death Dis. 2019 Jan 18;10(2):52. doi: 10.1038/s41419-018-1288-0.
Polycomb group family is a class of proteins that have important roles in both physiological and pathological processes, and its family member Chromobox homolog 8 (CBX8) regulates cell differentiation, aging, and cell cycle progression in numerous carcinomas; however, the effects and underlying mechanisms of CBX8 in hepatocellular carcinoma (HCC) are rarely reported. We found that CBX8 expression in clinical HCC specimens correlates inversely with patient survival. In HCC cells, we found that enforced overexpression of CBX8 induces epithelial-mesenchymal transition, invasive migration, and stem cell-like traits, which are associated with increased tumor growth and metastasis in mice. Conversely, CBX8 silencing inhibits the aggressive phenotype of HCC cells that have high CBX8 expression. Mechanistically, CBX8 modulates H3K27me3 in the gene promoter of bone morphogenetic protein 4 (BMP4), which is associated with active BMP4 transcription and, consequently, the activation of Smads and mitogen-activated protein kinases. BMP4 expression reverses the effects of CBX8 silencing in inhibiting epithelial-mesenchymal transition, stemness, and metastasis. Our results establish CBX8 as a critical driver of HCC stem cell-like and metastatic behaviors and characterize its role in modulating BMP4 expression. These findings have implications for the targeting of CBX8 as an approach to HCC prognosis and treatment.
多梳抑制复合物家族是一类在生理和病理过程中具有重要作用的蛋白质，其家族成员 Chromobox 同源物 8（CBX8）调节多种癌中的细胞分化、衰老和细胞周期进程；然而，CBX8 在肝细胞癌（HCC）中的作用和潜在机制很少有报道。我们发现 CBX8 在临床 HCC 标本中的表达与患者生存呈负相关。在 HCC 细胞中，我们发现强制过表达 CBX8 可诱导上皮-间充质转化、侵袭性迁移和干细胞样特征，这与小鼠中肿瘤生长和转移的增加有关。相反，CBX8 沉默抑制了具有高 CBX8 表达的 HCC 细胞的侵袭表型。从机制上讲，CBX8 调节骨形态发生蛋白 4（BMP4）基因启动子中的 H3K27me3，这与 BMP4 转录的激活以及随后 Smads 和丝裂原激活蛋白激酶的激活有关。BMP4 的表达逆转了 CBX8 沉默抑制上皮-间充质转化、干性和转移的作用。我们的研究结果确立了 CBX8 作为 HCC 干细胞样和转移行为的关键驱动因素，并描述了其在调节 BMP4 表达中的作用。这些发现对于将 CBX8 作为 HCC 预后和治疗的靶点具有重要意义。
