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首页> 外文期刊>EBioMedicine >The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network
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The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network

机译：CCDC170乳腺癌基因编码的蛋白质发挥功能来组织高尔基体-微管网络

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Genome-Wide Association Studies (GWAS) and subsequent fine-mapping studies (>50) have implicated single nucleotide polymorphisms (SNPs) located at the CCDC170/C6ORF97-ESR1 locus (6q25.1) as being associated with the risk of breast cancer. Surprisingly, our analysis using genome-wide differential allele-specific expression (DASE), an indicator for breast cancer susceptibility, suggested that the genetic alterations of CCDC170, but not ESR1, account for GWAS-associated breast cancer risk at this locus. Breast cancer-associated CCDC170 nonsense mutations and rearrangements have also been detected, with the latter being specifically implicated in driving breast cancer. Here we report that the wild type CCDC170 protein localizes to the region of the Golgi apparatus and binds Golgi-associated microtubules (MTs), and that breast cancer-linked truncations of CCDC170 result in loss of Golgi localization. Overexpression of wild type CCDC170 triggers Golgi reorganization, and enhances Golgi-associated MT stabilization and acetyltransferase ATAT1-dependent @a-tubulin acetylation. Golgi-derived MTs regulate cellular polarity and motility, and we provide evidence that dysregulation of CCDC170 affects polarized cell migration. Taken together, our findings demonstrate that CCDC170 plays an essential role in Golgi-associated MT organization and stabilization, and implicate a mechanism for how perturbations in the CCDC170 gene may contribute to the hallmark changes in cell polarity and motility seen in breast cancer.
机译：全基因组关联研究（GWAS）和后续的精细映射研究（> 50）暗示了CCDC170 / C6ORF97-ESR1基因座（6q25.1）处的单核苷酸多态性（SNP）与乳腺癌风险相关。出乎意料的是，我们使用全基因组差异等位基因特异性表达（DASE）（一种乳腺癌易感性指标）进行的分析表明，CCDC170而非ESR1的遗传变异是该位点与GWAS相关的乳腺癌风险的原因。还检测到了与乳腺癌相关的CCDC170废话突变和重排，后者与乳腺癌的发生密切相关。在这里，我们报告说，野生型CCDC170蛋白定位于高尔基体的区域并结合高尔基体相关的微管（MTs），并且与乳腺癌相关的CCDC170截短导致高尔基体定位的丧失。野生型CCDC170的过表达会触发高尔基体重组，并增强高尔基体相关的MT稳定性和乙酰转移酶ATAT1依赖的@ a-微管蛋白的乙酰化作用。高尔基体源性MTs调节细胞极性和运动性，我们提供证据表明CCDC170失调会影响极化细胞迁移。综上所述，我们的研究结果表明CCDC170在高尔基体相关的MT组织和稳定中起着至关重要的作用，并且暗示了CCDC170基因扰动如何有助于乳腺癌中细胞极性和运动性标志性变化的机制。

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