Phenotypic Screen Identifies JAK2 as a Major Regulator of FAT10 Expression

ACS Chem Biol. 2019 Dec 20;14(12):2538-2545. doi: 10.1021/acschembio.9b00667. Epub 2019 Dec 10.


FAT10 is a ubiquitin-like protein suggested to target proteins for proteasomal degradation. It is highly upregulated upon pro-inflammatory cytokines, namely, TNFα, IFNγ, and IL6, and was found to be highly expressed in various epithelial cancers. Evidence suggests that FAT10 is involved in cancer development and may have a pro-tumorigenic role. However, its biological role is still unclear, as well as its biochemical and cellular regulation. To identify pathways underlying FAT10 expression in the context of pro-inflammatory stimulation, which characterizes the cancerous environment, we implemented a phenotypic transcriptional reporter screen with a library of annotated compounds. We identified AZ960, a potent JAK2 inhibitor, which significantly downregulates FAT10 under pro-inflammatory cytokines induction, in an NFκB-independent manner. We validated JAK2 as a major regulator of FAT10 expression via knockdown, and we suggest that the transcriptional effects are mediated through pSTAT1/3/5. Overall, we have elucidated a pathway regulating FAT10 transcription and discovered a tool compound to chemically downregulate FAT10 expression, and to further study its biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Aminopyridines / pharmacology
  • HEK293 Cells
  • Humans
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism*
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / pharmacology
  • Ubiquitins / metabolism*


  • 5-fluoro-2-(1-(4-fluorophenyl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile
  • Aminopyridines
  • Protein Kinase Inhibitors
  • Pyrazoles
  • UBD protein, human
  • Ubiquitins
  • JAK2 protein, human
  • Janus Kinase 2