The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network
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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417302591 |
| _version_ | 1819051442675122176 |
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| author | Pengtao Jiang Yueran Li Andrey Poleshko Valentina Medvedeva Natalia Baulina Yongchao Zhang Yan Zhou Carolyn M. Slater Trinity Pellegrin Jason Wasserman Michael Lindy Andrey Efimov Mary Daly Richard A. Katz Xiaowei Chen |
| author_facet | Pengtao Jiang Yueran Li Andrey Poleshko Valentina Medvedeva Natalia Baulina Yongchao Zhang Yan Zhou Carolyn M. Slater Trinity Pellegrin Jason Wasserman Michael Lindy Andrey Efimov Mary Daly Richard A. Katz Xiaowei Chen |
| author_sort | Pengtao Jiang |
| collection | DOAJ |
| description | 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 α-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. |
| first_indexed | 2024-12-21T12:04:01Z |
| format | Article |
| id | doaj.art-b9d1dcb371e84004beb5648fab7f29b8 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-21T12:04:01Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-b9d1dcb371e84004beb5648fab7f29b82022-12-21T19:04:45ZengElsevierEBioMedicine2352-39642017-08-0122C284310.1016/j.ebiom.2017.06.024The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule NetworkPengtao Jiang0Yueran Li1Andrey Poleshko2Valentina Medvedeva3Natalia Baulina4Yongchao Zhang5Yan Zhou6Carolyn M. Slater7Trinity Pellegrin8Jason Wasserman9Michael Lindy10Andrey Efimov11Mary Daly12Richard A. Katz13Xiaowei Chen14Cancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesDepartment of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesDepartment of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesCancer Epigenetics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, United StatesGenome-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 α-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.http://www.sciencedirect.com/science/article/pii/S2352396417302591CCDC170/C6ORF97Golgi-associated microtubulesTubulin acetylationPolarized cell migrationGenome-wide association studies (GWAS)Differential allele specific expression (DASE) |
| spellingShingle | Pengtao Jiang Yueran Li Andrey Poleshko Valentina Medvedeva Natalia Baulina Yongchao Zhang Yan Zhou Carolyn M. Slater Trinity Pellegrin Jason Wasserman Michael Lindy Andrey Efimov Mary Daly Richard A. Katz Xiaowei Chen The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network EBioMedicine CCDC170/C6ORF97 Golgi-associated microtubules Tubulin acetylation Polarized cell migration Genome-wide association studies (GWAS) Differential allele specific expression (DASE) |
| title | The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network |
| title_full | The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network |
| title_fullStr | The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network |
| title_full_unstemmed | The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network |
| title_short | The Protein Encoded by the CCDC170 Breast Cancer Gene Functions to Organize the Golgi-Microtubule Network |
| title_sort | protein encoded by the ccdc170 breast cancer gene functions to organize the golgi microtubule network |
| topic | CCDC170/C6ORF97 Golgi-associated microtubules Tubulin acetylation Polarized cell migration Genome-wide association studies (GWAS) Differential allele specific expression (DASE) |
| url | http://www.sciencedirect.com/science/article/pii/S2352396417302591 |
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