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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.
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
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