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

• Main Authors: Liu, Bee Hui, Jobichen, Chacko, Chia, Brian C. S., 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 Shekhar, Tan, Hong Kee, Wu, Chan-Shuo, Li, Feng, Hill, Jeffrey, Joy, Joma, Chai, Li, Sivaraman, J., Tenen, Daniel G.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2020
• Subjects: Science::Biological sciences; SALL4; RBBp4/NuRD
• Online Access: https://hdl.handle.net/10356/137684
• Institution: Nanyang Technological University

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.