SDF-1 promotes migration, proliferation, and epithelial-mesenchymal plasticity of hepatocellular carcinoma cells via CXCR4-mediated histone deacetylation

Background The lethality of hepatocellular carcinoma (HCC) stems rom its propensity for distant metastasis and resistance to therapeutic agents, together making it a leading contributor to cancer mortality worldwide. Within the HCC microenvironment, cancer-associated fibroblasts (CAFs) promote tumor progression in part through secreted factors, among which stromal cell-derived factor-1 (SDF-1/CXCL12) signals through its receptor CXCR4, a chemokine receptor that is overexpressed in HCC and correlates with poor prognosis [13,17,38]. Aberrant histone deacetylation is a key epigenetic regulator of HCC progression [20,21,23]. Here, we aimed to investigate the role of fibroblast-derived SDF-1 in modulating histone acetylation through CXCR4 signaling and its impact on HCC cell behavior. Methods The role of SDF-1 in HCC was investigated using an indirect co-culture model of HepG2 cells and LX2 hepatic stellate cells. SDF-1, CXCR4, HDAC2, and HDAC6 were manipulated by knockdown and overexpression; cell behavior was assessed by Transwell migration, wound healing, CCK-8 viability, and flow cytometric apoptosis assays, and histone acetylation was examined by Western blotting, with the HDAC inhibitor vorinostat used as a comparator. Public single-cell RNA-sequencing data (GSE149614) were used to assess fibroblast SDF-1 enrichment. Results Our results showed that SDF-1 derived from LX2 cells promoted HepG2 cell migration and proliferation. SDF-1 treatment increased the expression of the mesenchymal markers Snail and Vimentin together with the epithelial marker E-cadherin, a pattern consistent with partial or hybrid epithelial-mesenchymal plasticity rather than a canonical EMT [19,39]. SDF-1 also suppressed global histone acetylation of H2A, H2B, H3, and H4 by upregulating the histone deacetylases HDAC2 and HDAC6. SDF-1 therefore suppresses histone acetylation and enhances HCC cell migration, proliferation, and epithelial-mesenchymal plasticity. Conclusion This study indicates that fibroblast-derived SDF-1 modulates histone acetylation and regulates HCC cell migration, proliferation, and epithelial-mesenchymal plasticity. Whether the SDF-1/CXCR4 axis is a viable therapeutic target remains to be tested in vivo. Trial registration Not applicable.