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

Hui Liu, Bee, Jobichen, Chacko, Chia, C S Brian, Chan, Tim Hon Man, Tang, Jing Ping, Chung, Theodora X Y, Li, Jia, Poulsen, Anders, Hung, Alvin W, Koh-Stenta, Xiaoying, Tan, Yaw Sing, Verma, Chandra S, Tan, Hong Kee, Wu, Chan-Shuo, Li, Feng, Hill, Jeffrey and others, (2018) Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 115 (30). pp. 7119-7128. ISSN 1091-6490

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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 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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Sussex Drug Discovery Centre
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Depositing User: Jeffrey Hill
Date Deposited: 07 Nov 2019 09:09
Last Modified: 15 Jan 2020 12:49

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