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Cited by 14Hedgehog Signaling Pathway StudiesWnt/β-catenin signaling in development and cancerCytokine Signaling Pathways and Interactions

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

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Carr, Ryan M., Romecin Duran, Paola A., Tolosa, Ezequiel J., Ma, Chenchao, Oseini, Abdul M., Moser, Catherine D., Banini, Bubu A., Huang, Jianbo +10 more·2020·Journal of Biological Chemistry
DOI 10.1074/jbc.ra119.011146PMC PMC7049957
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Abstract

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.

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  • Activated STAT3 can physically interact with Gli1 and lead to Gli1 enrichment in promoters of target genes controlled by Gli1-binding sites.

    “Aside from the direct regulation of Gli1 expression, recent evidence indicates that activated STAT3 can physically interact with Gli1 and lead to Gli1 enrichment in the promoters of target genes controlled by Gli1‐binding sites [32, 35].”

    From Saikosaponin b1 Attenuates Liver Fibrosis by Blocking STAT3/Gli1 Interaction and Inducing Gli1 Degradation (2025) · cites this paper as [35]

    In the ‘SULF2 promotes liver cancer through GLI1-STAT3 complex’ section (page unavailable), co-immunoprecipitation supports a physical interaction between STAT3 and GLI1 after SULF2 expression. The promoter-binding results show GLI1 enrichment under SULF2 expression, but STAT3 knockdown did not significantly reduce GLI1 enrichment at GLI1-binding sites. Thus, the paper does not establish that activated STAT3 causes GLI1 enrichment at those sites. (LLM, conf=0.87)

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Cited by

Sorted by citations

Authors
Carr, R. M., Romecin Duran, P. A., Tolosa, E. J., Ma, C., Oseini, A. M., Moser, C. D., Banini, B. A., Huang, J., Asumda, F., Dhanasekaran, R., Graham, R. P., Toruner, M. D., Safgren, S. L., Almada, L. L., Wang, S., Patnaik, M. M., Roberts, L. R., & Fernandez-Zapico, M. E.
Affiliations
Mayo Clinic (US)
Corresponding author
Roberts, Lewis R.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2020-02
Volume
295
Issue
9
Pages
2698-2712
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.ra119.011146
PMC
PMC7049957
OpenAlex
W3003658184
Cited by
14
References
3
Citations by year
2025: 2 · 2024: 3 · 2022: 2 · 2021: 4 · 2020: 3
FWCI
0.73
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
HHS | NIH | National Cancer Institute (CA165076, CA136526)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
SULF2, hepatocellular carcinoma, hepatocarcinogenesis, Gli1, STAT3, transcriptional complex, SOCS2, FLT3, diethylnitrosamine-induced liver cancer, transgenic mouse model, transcriptional regulation
MeSH terms
Zinc Finger Protein GLI1, Proto-Oncogene Mas, Animals, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Mice, Transgenic, Promoter Regions, Genetic, Protein Binding, Sulfatases, Trans-Activators, STAT Transcription Factors, STAT3 Transcription Factor, Mice, Carcinogenesis

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