Journal Article

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

Chung, Theodora X. Y., Chia, C. S. Brian, Liu, Bee Hui, Verma, Chandra S., Chai, Li, Tang, Jing Ping, Li, Feng, Yang, Henry, Tan, Yaw Sing, Hung, Alvin W., Chan, Tim Hon Man, Koh-Stenta, Xiaoying, Wu, Chan-Shuo, Li, Jia, Sivaraman, J., Tenen, Daniel G., Tan, Hong Kee, Poulsen, Anders, Joy, Joma, Jobichen, Chacko, Hill, Jeffrey

2018

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Addictions / Amino acid substitution / Amino acids / Animal models / Anticancer properties / Antineoplastic Agents - chemistry / Antineoplastic Agents - pharmacology / Antitumor activity / Biological Sciences / Cancer / Cancer therapies / Cell Line, Tumor / Crystal structure / Gene expression / Gene Expression Regulation - drug effects / Gene silencing / Gene therapy / Hepatocellular carcinoma / Histone deacetylase / Humans / Liver cancer / Malignancy / Medical Sciences / Neoplasm Proteins - chemistry / Neoplasm Proteins - genetics / Neoplasm Proteins - metabolism / Neoplasms - chemistry / Neoplasms - drug therapy / Neoplasms - genetics / Neoplasms - metabolism / NuRD protein / Peptides - chemistry / Peptides - pharmacology / Pharmacology / Pluripotency / PNAS Plus / Protein Structure, Quaternary / PTEN protein / Retinoblastoma-Binding Protein 4 - chemistry / Retinoblastoma-Binding Protein 4 - genetics / Retinoblastoma-Binding Protein 4 - metabolism / Stem cells / Survival / Transcription / Transcription Factors - chemistry / Transcription Factors - genetics / Transcription Factors - metabolism / Transcriptome - drug effects / Tumor suppressor genes / Tumors / Xenografts / Xenotransplantation