In:
Molecular Oncology, Wiley, Vol. 12, No. 8 ( 2018-08), p. 1358-1373
Kurzfassung:
The carboxyl‐terminal binding proteins (Ct BP ) are transcriptional corepressors that regulate the expression of multiple epithelial‐specific and pro‐apoptotic genes. Overexpression of Ct BP occurs in many human cancers where they promote the epithelial‐to‐mesenchymal transition, stem cell‐like features, and cell survival, while knockdown of Ct BP in tumor cells results in p53‐independent apoptosis. Ct BP s are recruited to their target genes by binding to a conserved PXDLS peptide motif present in multiple DNA ‐binding transcription factors. Disrupting the interaction between Ct BP and its transcription factor partners may be a means of altering Ct BP ‐mediated transcriptional repression and a potential approach for cancer therapies. However, small molecules targeting protein–protein interactions have traditionally been difficult to identify. In this study, we took advantage of the fact that Ct BP binds to a conserved peptide motif to explore the feasibility of using peptides containing the PXDLS motif fused to cell‐penetrating peptides ( CPP ) to inhibit Ct BP function. We demonstrate that these peptides disrupt the ability of Ct BP to interact with its protein partner, E1A, in an AlphaScreen assay. Moreover, these peptides can enter both lung carcinoma and melanoma cells, disrupt the interaction between Ct BP and a transcription factor partner, and inhibit Ct BP ‐mediated transcriptional repression. Finally, the constitutive expression of one such peptide, Pep1‐E1A‐ WT , in a melanoma cell line reverses Ct BP ‐mediated oncogenic phenotypes including proliferation, migration, and sphere formation and limits tumor growth in vivo . Together, our results suggest that CPP ‐fused PXDLS ‐containing peptides can potentially be developed into a research tool or therapeutic agent targeting Ct BP ‐mediated transcriptional events in various biological pathways.
Materialart:
Online-Ressource
ISSN:
1574-7891
,
1878-0261
DOI:
10.1002/mol2.2018.12.issue-8
DOI:
10.1002/1878-0261.12330
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2018
ZDB Id:
2322586-5
