An E2F1-HOXB9 transcriptional circuit is associated with breast cancer progression.
An E2F1-HOXB9 transcriptional circuit is associated with breast cancer progression.
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DOI：
10.1371/journal.pone.0105285
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kitagawa Y
中科院分区：
文献类型：
--
作者：
Zhussupova A;Hayashida T;Takahashi M;Miyao K;Okazaki H;Jinno H;Kitagawa Y
同源盒 B9 (HOXB9) 是同源盒基因家族的成员，在乳腺癌中过度表达，并通过刺激肿瘤微环境中的上皮间质转化和血管生成来促进肿瘤进展和转移。 HOXB9 激活 TGFβ-ATM 轴，导致检查点激活和 DNA 修复，从而在乳腺癌细胞中产生放射抗性。尽管详细报道了 HOXB9 在乳腺癌中的作用，但调节 HOXB9 转录的因素尚未得到广泛研究。在这里，我们发现了一种潜在机制，可能为乳腺癌治疗提出新的靶向策略。为了鉴定 HOXB9 启动子区域中的转录因子结合位点 (TFBS)，进行了双荧光素酶报告基因测定。通过 Q-PCR、电泳迁移率变动分析 (EMSA)、染色质免疫沉淀 (ChIP) 和突变分析检查可能直接附着到 HOXB9 TFBS 的候选蛋白质。从-404到-392的HOXB9启动子区域被鉴定为TFBS，并且E2F1是该区域的潜在结合候选者。通过 Q-PCR 在几种过表达 E2F1 的乳腺癌细胞系中观察到 E2F1 对 HOXB9 表达的诱导。通过荧光素酶、EMSA 和 ChIP 测定证实了 E2F1 对 HOXB9 转录的刺激作用及其结合 TFBS 的能力。对 139 份乳腺癌组织样本的免疫组织化学分析显示，E2F1 和 HOXB9 表达之间存在显着相关性 (p<0.001)。此外，CDK4/6 抑制剂抑制 E2F1 表达，并降低 HOXB9 及其下游靶基因的表达。我们的体外分析鉴定了 HOXB9 启动子区域的 TFBS，并表明 E2F1 是 HOXB9 表达的直接调节因子；这些数据支持我们在临床乳腺癌样本中发现的 E2F1 和 HOXB9 之间的强相关性。这些结果表明，靶向E2F1/HOXB9轴可能是控制或预防癌症进展和转移的新策略。
Homeobox B9 (HOXB9), a member of the homeobox gene family, is overexpressed in breast cancer and promotes tumor progression and metastasis by stimulating epithelial-to-mesenchymal transition and angiogenesis within the tumor microenvironment. HOXB9 activates the TGFβ-ATM axis, leading to checkpoint activation and DNA repair, which engenders radioresistance in breast cancer cells. Despite detailed reports of the role of HOXB9 in breast cancer, the factors that regulate HOXB9 transcription have not been extensively examined. Here we uncover an underlying mechanism that may suggest novel targeting strategies for breast cancer treatment. To identify a transcription factor binding site (TFBS) in the HOXB9 promoter region, a dual luciferase reporter assay was conducted. Protein candidates that may directly attach to a TFBS of HOXB9 were examined by Q-PCR, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), and mutation analysis. A HOXB9 promoter region from −404 to −392 was identified as TFBS, and E2F1 was a potential binding candidate in this region. The induction of HOXB9 expression by E2F1 was observed by Q-PCR in several breast cancer cell lines overexpressing E2F1. The stimulatory effect of E2F1 on HOXB9 transcription and its ability to bind the TFBS were confirmed by luciferase, EMSA and ChIP assay. Immunohistochemical analysis of 139 breast cancer tissue samples revealed a significant correlation between E2F1 and HOXB9 expression (p<0.001). Furthermore, a CDK4/6 inhibitor suppressed E2F1 expression and also reduced expression of HOXB9 and its downstream target genes. Our in vitro analysis identified the TFBS of the HOXB9 promoter region and suggested that E2F1 is a direct regulator of HOXB9 expression; these data support the strong correlation we found between E2F1 and HOXB9 in clinical breast cancer samples. These results suggest that targeting the E2F1/HOXB9 axis may be a novel strategy for the control or prevention of cancer progression and metastasis.
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影响因子：
37.3
作者：
Hoshino Y;Hayashida T;Hirata A;Takahashi H;Chiba N;Ohmura M;Wakui M;Jinno H;Hasegawa H;Maheswaran S;Suematsu M;Kitagawa Y
通讯作者：
Kitagawa Y
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7.3
作者：
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3.4
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Gorgoulis, V. G.
影响因子：
3.4
作者：
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通讯作者：
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5.1
作者：
Huang, Kai;Yuan, Rongfa;Shao, Jianghua
通讯作者：
Shao, Jianghua