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Understanding mechanism(s) of SALL4: structure and its interactions with epigenetic complexes, will lead to targeting SALL4 by blocking its protein-protein interaction.

SALL4 can function as a transcriptional repressor and activator through its interactions with both gene-repressing and activating epigenetic complexes. More specifically, SALL4 represses the expression of its target genes such as Phosphatase and Tensin homolog (PTEN) through its interaction with the Nucleosome Remodeling and Deacetylase complex (NuRD), a Histone Deacetylase (HDAC)-containing epigenetic repressor complex. SALL4 can also activate its target genes such as HOXA9 through its interaction with Mixed-Lineage Leukemia (MLL) protein, which is a key member of an epigenetic activator complex. We have further demonstrated that by blocking the interaction between SALL4 and NuRD with a peptide, we can inhibit its repression function. In addition to Pten and HoxA9, c-Myc is found to be a SALL4 target.
SALL4 diagnostics can benefit many cancer types where SALL4 is a targetable oncogene.

Structure of RBBp4–SALL4(1–12) complex and their binding affinity.

Antitumor activity of the candidate therapeutic peptide FFW.

Liu et al.  “Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide”, Proc Natl Acad Sci U S A, 2018.

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