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Proc Natl Acad Sci U S A. 2018 Jul 24;115(30):E7119-E7128. doi: 10.1073/pnas.1801253115. Epub 2018 Jul 5.

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide.

Author information

1
Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore.
2
Department of Biological Sciences, National University of Singapore, 117543 Singapore.
3
Experimental Therapeutics Centre, Agency for Science, Technology and Research, 138669 Singapore.
4
Department of Chemistry, National University of Singapore, 117543 Singapore.
5
Bioinformatics Institute, Agency for Science, Technology and Research, 138671 Singapore.
6
School of Biological Sciences, Nanyang Technological University, 637551 Singapore.
7
National University of Singapore, Graduate School for Integrative Sciences and Engineering, 117456 Singapore.
8
Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115; lchai@bwh.harvard.edu dbsjayar@nus.edu.sg csidgt@nus.edu.sg.
9
Department of Biological Sciences, National University of Singapore, 117543 Singapore; lchai@bwh.harvard.edu dbsjayar@nus.edu.sg csidgt@nus.edu.sg.
10
Cancer Science Institute of Singapore, National University of Singapore, 117599 Singapore; lchai@bwh.harvard.edu dbsjayar@nus.edu.sg csidgt@nus.edu.sg.
11
Havard Stem Cell Institute, Harvard Medical School, Boston, MA 02115.

Abstract

Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable.

KEYWORDS:

HCC; RBBp4/NuRD; SALL4; peptidomimetic; structural guided design

PMID:
29976840
PMCID:
PMC6065023
[Available on 2019-01-24]
DOI:
10.1073/pnas.1801253115
[Indexed for MEDLINE]

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