SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status.
SIAH ubiquitin ligases regulate breast cancer cell migration and invasion independent of the oxygen status.
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DOI：
10.1080/15384101.2015.1104441
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Algire C
中科院分区：
文献类型：
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作者：
Adam MG;Matt S;Christian S;Hess-Stumpp H;Haegebarth A;Hofmann TG;Algire C
七缺同源 (SIAH) 蛋白是进化保守的 RING 型 E3 泛素连接酶，负责调节 DNA 损伤反应、缺氧适应、细胞凋亡、血管生成和细胞增殖的关键分子的降解。许多研究表明 SIAH2 具有致瘤作用。在乳腺癌患者中，SIAH2 表达水平与癌症侵袭性和患者总体生存率相关。此外，SIAH 抑制可减少黑色素瘤的转移。 SIAH1 在乳腺癌中的作用仍不明确；致瘤和肿瘤抑制功能均已被报道。其他研究将 SIAH 连接酶分为促迁移或抗迁移，而其对转移的意义很大程度上未知。在这里，我们重新评估了 SIAH1 和 SIAH2 缺失对乳腺癌细胞系的影响，重点关注迁移和侵袭。我们成功地敲低了几种乳腺癌细胞系中的 SIAH1 和 SIAH2。在管腔型 MCF7 细胞中，这导致 SIAH 底物脯氨酰羟化酶结构域蛋白 3 (PHD3) 稳定并降低缺氧诱导因子 1α (HIF1α) 蛋白水平。 SIAH1 或 SIAH2 的敲低都会导致细胞凋亡增加和增殖减少，且效果相当。这些结果表明 SIAH1 在乳腺癌中的肿瘤促进作用与 SIAH2 类似。此外，SIAH1或SIAH2的缺失还导致乳腺癌细胞的细胞迁移和侵袭减少。 SIAH 敲低还通过显着降低 stathmin 的蛋白质水平（很可能是通过 p27Kip1）来控制微管动力学。总的来说，这些结果表明，两种 SIAH 连接酶都会促进癌细胞迁移表型，并可能导致乳腺癌转移。
Seven-in-absentia homolog (SIAH) proteins are evolutionary conserved RING type E3 ubiquitin ligases responsible for the degradation of key molecules regulating DNA damage response, hypoxic adaptation, apoptosis, angiogenesis, and cell proliferation. Many studies suggest a tumorigenic role for SIAH2. In breast cancer patients SIAH2 expression levels correlate with cancer aggressiveness and overall patient survival. In addition, SIAH inhibition reduced metastasis in melanoma. The role of SIAH1 in breast cancer is still ambiguous; both tumorigenic and tumor suppressive functions have been reported. Other studies categorized SIAH ligases as either pro- or antimigratory, while the significance for metastasis is largely unknown. Here, we re-evaluated the effects of SIAH1 and SIAH2 depletion in breast cancer cell lines, focusing on migration and invasion. We successfully knocked down SIAH1 and SIAH2 in several breast cancer cell lines. In luminal type MCF7 cells, this led to stabilization of the SIAH substrate Prolyl Hydroxylase Domain protein 3 (PHD3) and reduced Hypoxia-Inducible Factor 1α (HIF1α) protein levels. Both the knockdown of SIAH1 or SIAH2 led to increased apoptosis and reduced proliferation, with comparable effects. These results point to a tumor promoting role for SIAH1 in breast cancer similar to SIAH2. In addition, depletion of SIAH1 or SIAH2 also led to decreased cell migration and invasion in breast cancer cells. SIAH knockdown also controlled microtubule dynamics by markedly decreasing the protein levels of stathmin, most likely via p27Kip1. Collectively, these results suggest that both SIAH ligases promote a migratory cancer cell phenotype and could contribute to metastasis in breast cancer.