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

Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
Title:
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide
Other Titles:
PNAS
Publication Date:
05 July 2018
Citation:
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide 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, Joma Joy, Henry Yang, Li Chai, J. Sivaraman, Daniel G. Tenen Proceedings of the National Academy of Sciences Jul 2018, 115 (30) E7119-E7128; DOI: 10.1073/pnas.1801253115
Abstract:
SALL4 is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in HCC, a malignancy with no effective treatment. In cancer cells, SALL4 associates with 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 2.7Å, 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 uni-directional upregulation of transcripts, turning SALL4 a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23nM, and displays significant anti-tumor 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 caused massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as novel drug target and FFW as a viable drug candidate, and showcasing an effective strategy to accurately target oncogenes previously considered undruggable.
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PublisherCopyrights
Funding Info:
Singapore Ministry of Health's National Medical Research Council; National Research Foundation Singapore; Singapore Ministry of Education Tier-2 grant (WBS # R154000625112); A*STAR Biomedical Research Council (BMRC)
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