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|Title:||Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide||Authors:||Liu, Bee Hui
Chia, Brian C. S.
Chan, Tim Hon Man
Tang, Jing Ping
Chung, Theodora X. Y.
Hung, Alvin W.
Tan, Yaw Sing
Verma, Chandra Shekhar
Tan, Hong Kee
Tenen, Daniel G.
|Keywords:||Science::Biological sciences||Issue Date:||2018||Source:||Liu, B. H., Jobichen, C., Chia, B. C. S., Chan, T. H. M., Tang, J. P., Chung, T. X. Y., . . ., Tenen, D. G. (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, 115 (30), E7119-E7128. doi: 10.1073/pnas.1801253115||Journal:||Proceedings of the National Academy of Sciences of the United States of America||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.||URI:||https://hdl.handle.net/10356/137684||ISSN:||0027-8424||DOI:||10.1073/pnas.1801253115||Rights:||© 2018 The Author(s) (Published by National Academy of Sciences). All rights reserved.||Fulltext Permission:||none||Fulltext Availability:||No Fulltext|
|Appears in Collections:||SBS Journal Articles|
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