Editors' ChoiceCancer

Snail and HDAC1 target p53 for degradation

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Sci. Signal.  08 Nov 2016:
Vol. 9, Issue 453, pp. ec261
DOI: 10.1126/scisignal.aal3438

The transcription factor Snail promotes epithelial-to-mesenchymal transition (EMT), a process that regulates proper development but also confers metastatic and stemlike properties to cancer cells. Snail-mediated repression of the gene encoding epithelial lineage–associated marker E-cadherin involves the recruitment of histone deacetylases HDAC1 and HDAC2. Ni et al. found that a complex formed between Snail and HDAC1 also operates at the posttranslational level, promoting the deacetylation and degradation of the tumor suppressor protein p53. Bioinformatics analysis revealed decreased relapse-free survival in breast cancer patients whose tumors had high expression of Snail1 coincident with that of wild-type, but not mutant, TP53 (the gene encoding p53). Conditionally deleting Snail1 from mammary epithelial cells in the MMTV-PyMT mouse model of breast cancer inhibited the growth and metastatic progression of mammary tumors and increased the abundance of p53 in tumor cells. Isolated neoplastic mammary epithelial cells (NECs) isolated from Snail1-knockout tumors had greater luminal differentiation and fewer markers associated with tumor-initiating cells than did those from wild-type tumors. Also in isolated NECs, Snail1 expression correlated with decreased half-life and increased deacetylation and ubiquitylation of p53. Immunoprecipitation analyses using wild-type and mutant proteins in transfected human breast cancer cells revealed that Snail interacted with wild-type more than with mutant p53 and recruited HDAC1 through a domain that is associated with Snail’s transcriptional repression activity. Deleting TP53 in Snail-null tumors restored tumorigenic phenotypes in mammary tissue in MMTV-PyMT mice. The findings show that, in a similar manner to its function at the transcriptional level, Snail recruits HDAC1 to repress a target (p53) at the posttranslational level. Thus, disrupting the interaction between Snail and p53 may be therapeutic in some breast cancer patients.

T. Ni, X.-Y. Li, N. Lu, T. An, Z.-P. Liu, R. Fu, W.-C. Lv, Y.-W. Zhang, X.-J. Xu, R. G. Rowe, Y.-S. Lin, A. Scherer, T. Feinberg, X.-Q. Zheng, B.-A. Chen, X. S. Liu, Q.-L. Guo, Z.-Q. Wu, S. J. Weiss, Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer. Nat. Cell Biol. 18, 1221–1232 (2016). [PubMed]