Reference - Detail
RRC ID | 58296 |
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Author | Jain PB, Guerreiro PS, Canato S, Janody F. |
Title | The spectraplakin Dystonin antagonizes YAP activity and suppresses tumourigenesis. |
Journal | Sci Rep |
Abstract |
Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast. However, little is known about its role in carcinogenesis. In this report, we demonstrate that Dystonin is a candidate tumour suppressor in breast cancer and provide an underlying molecular mechanism. We show that in MCF10A cells, Dystonin is necessary to restrain cell growth, anchorage-independent growth, self-renewal properties and resistance to doxorubicin. Strikingly, while Dystonin maintains focal adhesion integrity, promotes cell spreading and cell-substratum adhesion, it prevents Zyxin accumulation, stabilizes LATS and restricts YAP activation. Moreover, treating DST-depleted MCF10A cells with the YAP inhibitor Verteporfin prevents their growth. In vivo, the Drosophila Dystonin Short stop also restricts tissue growth by limiting Yorkie activity. As the two Dystonin isoforms BPAG1eA and BPAG1e are necessary to inhibit the acquisition of transformed features and are both downregulated in breast tumour samples and in MCF10A cells with conditional induction of the Src proto-oncogene, they could function as the predominant Dystonin tumour suppressor variants in breast epithelial cells. Thus, their loss could deem as promising prognostic biomarkers for breast cancer. |
Volume | 9(1) |
Pages | 19843 |
Published | 2019-12-27 |
DOI | 10.1038/s41598-019-56296-z |
PII | 10.1038/s41598-019-56296-z |
PMID | 31882643 |
PMC | PMC6934804 |
MeSH | Animals Breast Neoplasms / genetics* Breast Neoplasms / metabolism Breast Neoplasms / pathology Cell Adhesion / genetics Cell Line Cell Proliferation / genetics Cell Transformation, Neoplastic / genetics* Cell Transformation, Neoplastic / metabolism Drosophila Drosophila Proteins / antagonists & inhibitors Drosophila Proteins / genetics* Drosophila Proteins / metabolism Epithelial Cells / drug effects Epithelial Cells / metabolism Female Genes, Tumor Suppressor* HEK293 Cells Humans Microfilament Proteins / genetics* Microfilament Proteins / metabolism Nuclear Proteins / antagonists & inhibitors Nuclear Proteins / genetics* Nuclear Proteins / metabolism Photosensitizing Agents / pharmacology Protein Isoforms / genetics Protein Isoforms / metabolism Proto-Oncogene Mas RNA Interference Trans-Activators / antagonists & inhibitors Trans-Activators / genetics* Trans-Activators / metabolism Verteporfin / pharmacology YAP-Signaling Proteins |
IF | 3.998 |
Times Cited | 0 |
Resource | |
Drosophila | 4005R-2 |