SDF-1 promotes migration, proliferation, and epithelial-mesenchymal plasticity of hepatocellular carcinoma cells via CXCR4-mediated histone deacetylation
4 affiliations
- 1Hepatobiliary Pancreatic Surgery, Jinjiang Municipal Hospital, Quanzhou City, Fujian Province, China; Corresponding author. Hepatobiliary Pancreatic Surgery, Jinjiang Municipal Hospital, Fujian, No. 16, Luoshan Section, Jinguang Road, Jinjiang City, Quanzhou City, Fujian Province, 362200, China.
- 2Quanzhou Medical College, Quanzhou City, Fujian Province, China
- 3Hepatobiliary Pancreatic Surgery, Jinjiang Municipal Hospital, Quanzhou City, Fujian Province, China
- 4Interventional Vascular Surgery, Jinjiang Municipal Hospital, Quanzhou City, Fujian Province, China; Anorectal Surgery, Jinjiang Municipal Hospital, Quanzhou City, Fujian Province, China
Abstract
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.
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BibTeX
@article{cai2026sdf1,
title = {{SDF-1 promotes migration, proliferation, and epithelial-mesenchymal plasticity of hepatocellular carcinoma cells via CXCR4-mediated histone deacetylation}},
author = {Siyi Cai and Tianshen Xiao and Zhongfei Luo and Lin Hu and Maoyi Chen and Chunhuai You},
journal = {Journal of Radiation Research and Applied Sciences},
year = {2026},
month = oct,
doi = {10.1016/j.jrras.2026.102738},
url = {https://doi.org/10.1016/j.jrras.2026.102738},
note = {CC BY},
}
RIS
TY - JOUR
TI - SDF-1 promotes migration, proliferation, and epithelial-mesenchymal plasticity of hepatocellular carcinoma cells via CXCR4-mediated histone deacetylation
AU - Siyi Cai
AU - Tianshen Xiao
AU - Zhongfei Luo
AU - Lin Hu
AU - Maoyi Chen
AU - Chunhuai You
PY - 2026
DA - 2026/10/30
JO - Journal of Radiation Research and Applied Sciences
DO - 10.1016/j.jrras.2026.102738
UR - https://doi.org/10.1016/j.jrras.2026.102738
AB - 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.
SN - 2314-7164
SN - 1687-8507
ER -