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.

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…Interestingly, these investigators found that the production of CXCL1 from TRAMP-G2LG cancer cells reached ∼4 ng/ml, similar to the concentration of CXCL1 that inhibited ASMC migration in our study. These results suggest that, although known as a mediator of cell chemotaxis (16,17), at specific concentrations CXCL1 may act as a negative regulator of cell migration/invasion both in vitro and in vivo.…”

“…Although primarily known as a potent inducer of neutrophil chemotaxis (16), CXCL1 was shown to induce cancer cell invasion (17) and endothelial (18) and epithelial cell migration (19). CXCL1 facilitates its signaling by binding to its putative receptor, the chemokine receptor CXCR2, although it also was found to bind to CXCR1, albeit with lower affinity (20).…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…On the other hand, CCL2 prevents apoptosis of neutrophils [245] and activates neutrophils in the pre-metastatic lung towards an anti-tumor phenotype where they produce H 2 O 2 to kill disseminated tumor cells [32,66], suggesting a dual role of this chemokine. Also, CXCL1 was shown to promote tumor cell proliferation [246], tumor angiogenesis [247], invasion and migration [248], in addition to its ability to recruit and activate neutrophils [249]. CXCL1 was shown to be involved in a paracrine network mediating both metastatic progression and chemoresistance [250].…”

CXCL1 expression is correlated with Snail expression and affects the prognosis of patients with gastric cancer

“…In addition, CXCL1 activates nuclear factor (NF)-κB signaling through epidermal growth factor receptor-transactivated Akt and contributes to CXCR2-mediated ovarian cancer progression (6). CXCL1 was also found to contribute to prostate tumor cell migration and invasion through the activation of NF-κB (7). In GC, overexpression of CXCL1 and its receptor CXCR2 were found to be associated with tumor metastasis and a poor prognosis (8).…”