The extracellular sulfatase SULF2 promotes liver tumorigenesis by stimulating assembly of a promoter-looping GLI1-STAT3 transcriptional complex

J Biol Chem. 2020 Feb 28;295(9):2698-2712. doi: 10.1074/jbc.RA119.011146. Epub 2020 Jan 27.


The expression of the extracellular sulfatase SULF2 has been associated with increased hepatocellular carcinoma (HCC) growth and poor patient survival. However, the molecular mechanisms underlying SULF2-associated tumor growth remain unclear. To address this gap, here we developed a transgenic mouse overexpressing Sulf2 in hepatocytes under the control of the transthyretin promoter. In this model, Sulf2 overexpression potentiated diethylnitrosamine-induced HCC. Further analysis indicated that the transcription factor GLI family zinc finger 1 (GLI1) mediates Sulf2 expression during HCC development. A cross of the Sulf2-overexpressing with Gli1-knockout mice revealed that Gli1 inactivation impairs SULF2-induced HCC. Transcriptomic analysis revealed that Sulf2 overexpression is associated with signal transducer and activator of transcription 3 (STAT3)-specific gene signatures. Interestingly, the Gli1 knockout abrogated SULF2-mediated induction of several STAT3 target genes, including suppressor of cytokine signaling 2/3 (Socs2/3); Pim-1 proto-oncogene, Ser/Thr kinase (Pim1); and Fms-related tyrosine kinase 4 (Flt4). Human orthologs were similarly regulated by SULF2, dependent on intact GLI1 and STAT3 functions in HCC cells. SULF2 overexpression promoted a GLI1-STAT3 interaction and increased GLI1 and STAT3 enrichment at the promoters of their target genes. Interestingly, the SULF2 overexpression resulted in GLI1 enrichment at select STAT3 consensus sites, and vice versa. siRNA-mediated STAT3 or GLI1 knockdown reduced promoter binding of GLI1 and STAT3, respectively. Finally, chromatin-capture PCR confirmed long-range co-regulation of SOCS2 and FLT3 through changes in promoter conformation. These findings define a mechanism whereby SULF2 drives HCC by stimulating formation of a GLI1-STAT3 transcriptional complex.

Keywords: GLI1; STAT transcription factor; STAT3; SULF2; carcinogenesis; gene regulation; gene transcription; hepatocellular carcinoma; promoter conformation; tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinogenesis
  • Carcinoma, Hepatocellular / etiology*
  • Humans
  • Liver Neoplasms / etiology*
  • Mice
  • Mice, Transgenic
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Mas
  • STAT Transcription Factors
  • STAT3 Transcription Factor / metabolism*
  • Sulfatases / metabolism
  • Sulfatases / physiology*
  • Trans-Activators
  • Zinc Finger Protein GLI1 / metabolism*


  • MAS1 protein, human
  • Proto-Oncogene Mas
  • STAT Transcription Factors
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Trans-Activators
  • Zinc Finger Protein GLI1
  • Sulf2 protein, mouse
  • Sulfatases