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Edited by Riccardo Dalla-Favera, Columbia University Medical Center, New York, NY, and approved June 4, 2018 (received for review January 22, 2018)
Significance
Hepatocellular carcinoma (HCC) is leading cause of death due to late discovery and lack of effective treatment. The finding of the Sal-like 4 (SALL4)–NuRD interaction in HCC opens a new therapeutic direction targeting an epigenetic regulator. Here, we identified the SALL4–NuRD binding site through structural resolution of the crystal complex, providing valuable insight for the development of antagonists against this interaction. Our subsequent design of a therapeutic peptide has demonstrated the possibility to develop a first-in-class drug targeting the SALL4–NuRD interaction in HCC. Furthermore, we discovered that the therapeutic peptide exhibits robust antitumor properties and works by inhibiting the repressive function of SALL4. Our work could also be beneficial to a broad range of solid cancers and leukemic malignancies with elevated SALL4.
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.
Footnotes
↵1B.H.L. and C.J. contributed equally to this work.
- ↵2To whom correspondence may be addressed. Email: lchai{at}bwh.harvard.edu, dbsjayar{at}nus.edu.sg, or csidgt{at}nus.edu.sg.
Author contributions: B.H.L., C.J., C.S.B.C., C.S.V., J.H., J.J., H.Y., L.C., J.S., and D.G.T. designed research; B.H.L., T.H.M.C., J.P.T., T.X.Y.C., A.W.H., X.K.-S., Y.S.T., H.K.T., and F.L. performed research; B.H.L., C.J., C.S.B.C., and T.X.Y.C. contributed new reagents/analytic tools; B.H.L., C.J., J.L., A.P., and C.-S.W. analyzed data; and B.H.L., C.J., C.S.B.C., A.P., L.C., J.S., and D.G.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The coordinates and structure factors of the RBBp4–SALL4 crystal complex have been deposited in the RCSB database, https://www.wwpdb.org/ (PBD ID code 5XWR). The RNA-seq and ChIP-seq data have been deposited in the Gene Expression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession no. GSE112729).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1801253115/-/DCSupplemental.
Published under the PNAS license.
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Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
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