Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 30, Pages E7119-E7128Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1801253115
Keywords
SALL4; RBBp4/NuRD; peptidomimetic; HCC; structural guided design
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Funding
- Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research Investigator Award
- National Research Foundation Singapore
- Singapore Ministry of Education under its Research Centres of Excellence initiative
- Singapore Ministry of Education-Tier-2 Grant WBS [R154000625112]
- A*STAR Biomedical Research Council
- NIH [PO1HL095489]
- Leukemia and Lymphoma Society
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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 angstrom, 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 upregulation 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.
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