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

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.

journal_name

Proc Natl Acad Sci U S A

journal_title

Proceedings of the National Academy of Sciences of the United States of America

authors

Liu BH,Jobichen C,Chia CSB,Chan THM,Tang JP,Chung TXY,Li J,Poulsen A,Hung AW,Koh-Stenta X,Tan YS,Verma CS,Tan HK,Wu CS,Li F,Hill J,Joy J,Yang H,Chai L,Sivaraman J,Tenen DG

doi

10.1073/pnas.1801253115

subject

Has Abstract

pub_date

2018-07-24 00:00:00

pages

E7119-E7128

issue

30

eissn

0027-8424

issn

1091-6490

pii

1801253115

journal_volume

115

pub_type

杂志文章

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