Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and the fifth most common cancer in the world
Chromobox homolog 8 (CBX8) is highly expressed in HCC, and its expression is positively correlated with distant metastasis, and inversely correlated with overall survival
We examined the potential correlation of CBX8 expression with HCC disease parameters and tumor morphology
Summary
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death and the fifth most common cancer in the world. The polycomb group proteins, first discovered in Drosophila, are essential regulators of cell proliferation and differentiation, which are often deregulated in human cancers and contribute to the development of cancer[4,5]. CBX8 regulates numerous target genes that are important for cell growth and survival, including the tumor suppressor gene INK4a/ARF locus[6], which is involved in cellfate decisions, and AF9, which is implicated in the development of acute leukemia[7]. CBX8 is upregulated in colorectal cancer, and CBX8 overexpression indicates poor prognosis[9]. Evidence suggests that CBX8 expression is correlated with the tumor generation and development, few studies have focused on the function and mechanism of CBX8 in HCC
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