CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation
CXCL1/GROα increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-κB/HDAC1 epigenetic regulation
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DOI：
10.1093/carcin/bgs299
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发表时间：
2012-12-01
期刊：
影响因子：
4.7
通讯作者：
Hsu, Ya-Ling
中科院分区：
文献类型：
--
作者：
Kuo, Po-Lin;Shen, Kun-Hung;Hsu, Ya-Ling
炎症性肿瘤微环境在癌症的发展中起着关键作用。炎性细胞因子如CXCL 1/GRO通过增加肿瘤血管生成发挥促癌活性。然而，CXCL 1/GRO是否也在前列腺癌的进展中发挥作用，特别是在高度侵袭性去势抵抗性前列腺癌（CRPC）中，尚未研究。我们探讨了CXCL 1/GRO是否增强PC-3和DU 145 CRPC中的细胞迁移和侵袭。CXCL 1/GRO诱导PC-3和DU 145癌症进展与AKT活化和IB激酶（IKK）磷酸化增加相关，导致核因子-κ B（NF-B）活化。活化的NF-B与组蛋白去乙酰化酶1（HDAC 1）相互作用形成基因沉默复合物，其通过降低fibulin-1D启动子的NF-B结合位点上的组蛋白H3和H4的乙酰化来抑制fibulin-1D的表达。通过小发夹RNA（shRNA）阻断AKT 2降低IKK磷酸化、NF-B核转位和细胞迁移，表明AKT在CXCL 1/GRO介导的NF-B活化和细胞迁移中是必需的。此外，NF-B和HDAC 1 shRNA降低了CXCL 1/GRO对纤蛋白-1D下调、迁移和侵袭的影响，表明NF-B/HDAC 1复合物也参与了CXCL 1/GRO介导的癌症进展。我们的研究结果提供了CXCL 1/GRO降低前列腺癌细胞中fibulin-1D表达的第一个证据，也揭示了CXCL 1/GRO通过AKT途径调节NF-B激活的机制的新见解。我们的研究结果还清楚地表明，NF-B和HDAC 1的合作通过表观遗传修饰调节fibulin-1D的表达。我们的研究表明，抑制CXCL 1/GRO介导的AKT/NF-B信号可能是CRPC的一个有吸引力的治疗靶点。
Inflammatory tumor microenvironments play pivotal roles in the development of cancer. Inflammatory cytokines such as CXCL1/GRO exert cancer-promoting activities by increasing tumor angiogenesis. However, whether CXCL1/GRO 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/GRO enhances cell migration and invasion in PC-3 and DU145 CRPC. Induction of PC-3 and DU145 cancer progression by CXCL1/GRO is associated with increased AKT activation and IB kinase (IKK) phosphorylation, resulting in nuclear factor-kappaB (NF-B) activation. Activated NF-B 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-B-binding site of the fibulin-1D promoter. Blockade of AKT2 by small hairpin RNA (shRNA) decreases IKK phosphorylation, NF-B nuclear translocation and cell migration, indicating that AKT is required in CXCL1/GRO-mediated NF-B activation and cell migration. In addition, NF-B and HDAC1 shRNA decrease the effect of CXCL1/GRO on fibulin-1D downregulation, migration and invasion, suggesting that the NF-B/HDAC1 complex is also involved in CXCL1/GRO-mediated cancer progression. Our findings provide the first evidence that CXCL1/GRO decreases fibulin-1D expression in prostate cancer cells and also reveals novel insights into the mechanism by which CXCL1/GRO regulates NF-B activation through the AKT pathway. Our results also clearly establish that co-operation of NF-B and HDAC1 regulates fibulin-1D expression by epigenetic modification. Our study suggests that inhibition of CXCL1/GRO-mediated AKT/NF-B signaling may be an attractive therapeutic target for CRPC.