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.
Highlights
Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast
These domains include Calponin-homology domains (CH), which bind to actin filaments, a plakin repeat region, which links to intermediate filaments (IF-BD), a growth-arrest specific 2-related (GAR) microtubule-binding domain, an EF-hand calcium-binding domain, and a spectrin-repeat rod[30,31]
MCF10A-Estrogen receptor (ER)-Src cells in which we forced the expression of DST using the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based activation system[40] were unable to grow
Summary
Aberrant expression of the Spectraplakin Dystonin (DST) has been observed in various cancers, including those of the breast. 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 Their loss could deem as promising prognostic biomarkers for breast cancer. Two genes are known to encode for spectraplakins: microtubule and actin crosslinking factor 1 (MACF1; known as actin crosslinking factor 7, ACF7) and Dystonin (DST; www.nature.com/scientificreports known as bullous pemphigoid antigen 1, BPAG1)[30] They are evolutionary conserved proteins and give rise to differentially spliced variants resulting in distinct isoforms. As the tumour suppressor function of DST involves the shorter BPAG1eA and/or BPAG1e isoforms, they could be used as prognostic biomarkers for breast cancer
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