title: CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation.
abstract: Inflammatory tumor microenvironments play pivotal roles in the development of cancer. Inflammatory cytokines such as CXCL1/GROα exert cancer-promoting activities by increasing tumor angiogenesis. However, whether CXCL1/GROα also plays a role in the progression of prostate cancer, particularly in highly invasive castration-resistant prostate cancer (CRPC), has not been investigated. We explored whether CXCL1/GROα enhances cell migration and invasion in PC-3 and DU145 CRPC. Induction of PC-3 and DU145 cancer progression by CXCL1/GROα is associated with increased AKT activation and IκB kinase α (IKKα) phosphorylation, resulting in nuclear factor-kappaB (NF-κB) activation. Activated NF-κB interacts with histone deacetylase 1 (HDAC1) to form a gene-silencing complex, which represses the expression of fibulin-1D by decreasing the acetylation of histone H3 and H4 on the NF-κB-binding site of the fibulin-1D promoter. Blockade of AKT2 by small hairpin RNA (shRNA) decreases IKKα phosphorylation, NF-κB nuclear translocation and cell migration, indicating that AKT is required in CXCL1/GROα-mediated NF-κB activation and cell migration. In addition, NF-κB and HDAC1 shRNA decrease the effect of CXCL1/GROα on fibulin-1D downregulation, migration and invasion, suggesting that the NF-κB/HDAC1 complex is also involved in CXCL1/GROα-mediated cancer progression. Our findings provide the first evidence that CXCL1/GROα decreases fibulin-1D expression in prostate cancer cells and also reveals novel insights into the mechanism by which CXCL1/GROα regulates NF-κB activation through the AKT pathway. Our results also clearly establish that co-operation of NF-κB and HDAC1 regulates fibulin-1D expression by epigenetic modification. Our study suggests that inhibition of CXCL1/GROα-mediated AKT/NF-κB signaling may be an attractive therapeutic target for CRPC.
authors.affiliation: Institute of Clinical Medicine,  College of Medicine,  Kaohsiung Medical University, Kaohsiung 807,  Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.forename: Kun-Hung
authors.initials: KH
authors.lastname: Shen
authors.forename: Shun-Hsing
authors.initials: SH
authors.lastname: Hung
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
mesh_terms: D002135:Calcium-Binding Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D054360:Chemokine CXCL1 / Q000502:physiology*; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D056284:Histone Deacetylase 1 / Q000502:physiology*; D006801:Humans; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D015398:Signal Transduction
chemical_list: C475829:CXCL1 protein, human; D002135:Calcium-Binding Proteins; D054360:Chemokine CXCL1; D016328:NF-kappa B; C060820:fibulin; D051057:Proto-Oncogene Proteins c-akt; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1