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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Cell Line, Tumor
  • Gene Expression Regulation / drug effects*
  • Humans
  • Neoplasm Proteins* / chemistry
  • Neoplasm Proteins* / genetics
  • Neoplasm Proteins* / metabolism
  • Neoplasms* / chemistry
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Neoplasms* / metabolism
  • Peptides* / chemistry
  • Peptides* / pharmacology
  • Protein Structure, Quaternary
  • Retinoblastoma-Binding Protein 4 / chemistry
  • Retinoblastoma-Binding Protein 4 / genetics
  • Retinoblastoma-Binding Protein 4 / metabolism
  • Transcription Factors* / chemistry
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • Transcriptome / drug effects*

Substances

  • Antineoplastic Agents
  • Neoplasm Proteins
  • Peptides
  • RBBP4 protein, human
  • Retinoblastoma-Binding Protein 4
  • SALL4 protein, human
  • Transcription Factors

Associated data

  • PDB/5XWR