1. Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide.
- Author
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Bee Hui Liu, Jobichen, Chacko, Chia, C. S. Brian, Hon Man Chan, Tim, Jing Ping Tang, Chung, Theodora X. Y., Jia Li, Poulsen, Anders, Hung, Alvin W., Xiaoying Koh-Stenta, Yaw Sing Tan, Verma, Chandra S., Hong Kee Tan, Chan-Shuo Wu, Feng Li, Hill, Jeffrey, Joy, Joma, Yang, Henry, Li Chai, and Sivaraman, J.
- Subjects
GENE targeting ,TRANSCRIPTOMES ,STEM cells ,LIVER cancer ,DEACETYLASES - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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