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
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.
This research is supported by the Singapore Ministry of Health’s National Medical Research Council under itsSingapore Translational Research Investigator Award, and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative. J.S. received funding from Singapore Ministry of Education–Tier-2 Grant WBS R154000625112 in support of this project. C.S.B.C., A.P., A.W.H., X.K.-S., J.H. and J.J. thank the A*STAR Biomedical Research Council for funding. L.C. was supported by NIH Grant PO1HL095489 and a research fund from the Leukemia and Lymphoma Society.
The full paper is available for download at the publisher's URL here: https://doi.org/10.1073/pnas.1801253115