eLife (Dec 2015)

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

  • Miyuki Suzawa,
  • Diego A Miranda,
  • Karmela A Ramos,
  • Kenny K-H Ang,
  • Emily J Faivre,
  • Christopher G Wilson,
  • Laura Caboni,
  • Michelle R Arkin,
  • Yeong-Sang Kim,
  • Robert J Fletterick,
  • Aaron Diaz,
  • John S Schneekloth Jr,
  • Holly A Ingraham

DOI
https://doi.org/10.7554/eLife.09003
Journal volume & issue
Vol. 4

Abstract

Read online

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.

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