title: Histone deacetylase inhibitors induce CXCR4 mRNA but antagonize CXCR4 migration.
abstract: The stromal cell-derived factor-1α SDF-1α (CXCL12)/CXCR4 axis has been linked to poor prognosis in some cancers. As histone deacetylase inhibitors (HDIs) exert antitumor effects by targeting proteins affecting cell migration, we sought to evaluate the effects of the HDIs apicidin, vorinostat, entinostat (MS-275) and romidepsin on the expression and function of CXCR4 in human cancer cell lines. After treatment with romidepsin, CXCR4 mRNA expression increased 12-fold in UOK121 renal cancer cells, 16-fold in H460 non-small cell cancer cells and 4-fold in SF295 glioma cells; treatment with other HDIs yielded similar effects. CXCR4 induction was not observed in MCF7 breast cancer cells or SW620 colon cancer cells. To evaluate the corresponding functional increase, the effect of CXCR4 ligand, CXCL12, on ERK1/2, STAT3 and c-SRC activation and cell migration was examined in UOK121, SF295 and H460 cells. Alone, the HDIs increased pERK1/2, while reducing pSTAT-3 and pSRC. Following CXCL12 exposure, pERK1/2 induction was maintained, but STAT3 and SRC phosphorylation was impaired. These findings resulted in reduced basal and CXCL12-mediated cell migration. In conclusion, HDIs upregulated CXCR4 mRNA expression but impaired CXCL12-dependent signaling cascades through STAT3 and c-SRC, suggesting a potential role for HDIs in delaying or preventing metastatic processes in solid tumors.
authors.affiliation: Medical Oncology Branch, National Cancer Institute; Bethesda, MD, USA.
authors.forename: Caterina
authors.initials: C
authors.lastname: Ierano
authors.forename: Agnes
authors.initials: A
authors.lastname: Basseville
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.forename: Zhirong
authors.initials: Z
authors.lastname: Zhan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Robey
authors.forename: Julia
authors.initials: J
authors.lastname: Wilkerson
authors.forename: Susan E
authors.initials: SE
authors.lastname: Bates
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
mesh_terms: D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D054377:Chemokine CXCL12; D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D051417:Focal Adhesion Kinase 1; D016392:Proto-Oncogene Proteins pp60(c-src); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3