Format

Send to

Choose Destination
Elife. 2015 Dec 11;4. pii: e09003. doi: 10.7554/eLife.09003.

A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States.
2
Small Molecule Discovery Center, Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, United States.
3
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States.
4
Chemical Biology Laboratory, National Cancer Institute, Frederick, United States.
5
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, United States.

Abstract

SUMO-modification of nuclear proteins has profound effects on gene expression. However, non-toxic chemical tools that modulate sumoylation in cells are lacking. Here, to identify small molecule sumoylation inhibitors we developed a cell-based screen that focused on the well-sumoylated substrate, human Liver Receptor Homolog-1 (hLRH-1, NR5A2). Our primary gene-expression screen assayed two SUMO-sensitive transcripts, APOC3 and MUC1, that are upregulated by SUMO-less hLRH-1 or by siUBC9 knockdown, respectively. A polyphenol, tannic acid (TA) emerged as a potent sumoylation inhibitor in vitro (IC50 = 12.8 µM) and in cells. TA also increased hLRH-1 occupancy on SUMO-sensitive transcripts. Most significantly, when tested in humanized mouse primary hepatocytes, TA inhibits hLRH-1 sumoylation and induces SUMO-sensitive genes, thereby recapitulating the effects of expressing SUMO-less hLRH-1 in mouse liver. Our findings underscore the benefits of phenotypic screening for targeting post-translational modifications, and illustrate the potential utility of TA for probing the cellular consequences of sumoylation.

KEYWORDS:

NASH; NR5As; cell biology; human; human biology; medicine; mouse; phenotypic screen; primary hepatocytes; sumoylation; tannic acid

PMID:
26653140
PMCID:
PMC4749390
DOI:
10.7554/eLife.09003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center