Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide.pdf (2.02 MB)
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
journal contribution
posted on 2023-06-09, 19:33 authored by Bee Hui Liu, Chacko Jobichen, C S Brian Chia, Tim Hon Man Chan, Jing Ping Tang, Theodora X Y Chung, Jia Li, Anders Poulsen, Alvin W Hung, Xiaoying Koh-Stenta, Yaw Sing Tan, Chandra S Verma, Hong Kee Tan, Chan-Shuo Wu, Feng Li, Jeffrey Hill, othersSal-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.
History
Publication status
- Published
File Version
- Published version
Journal
Proceedings of the National Academy of Sciences of the United States of America (PNAS)ISSN
1091-6490Publisher
National Academy of SciencesExternal DOI
Issue
30Volume
115Page range
7119-7128Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Sussex Drug Discovery Centre Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-11-07First Open Access (FOA) Date
2019-11-07First Compliant Deposit (FCD) Date
2019-11-06Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC