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https://hdl.handle.net/10356/137684
Title: | Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide | 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. |
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 | Schools: | School of Biological Sciences | 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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