Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.1.6.1 (
sulfatase
)
3,205
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Human
sulfatase
-1 (hSulf-1) has been shown to desulfate cellular heparin sulfate proteoglycans and modulate several growth factors and cytokines. However, hSulf-1 has not been previously shown to mediate the
signal transducer and activator of transcription 3
(
stat3
) signaling pathway, which is known to regulate cell proliferation, motility and apoptosis. The present study investigated the role of hSulf-1 in
stat3
signaling in hepatocellular cancer. hSulf-1 expression vector and
stat3
small interfering RNA (siRNA) were constructed to control the expression of hSulf-1 and
stat3
in HepG2 cells. hSulf-1 was found to inhibit the phosphorylation of
stat3
and downregulate its targeted protein. MTT and Transwell chamber assays, as well as Annexin V/propidium iodide double-staining methods, were used to examine the effects of hSulf-1 on
stat3
-mediated motility, proliferation and apoptosis in HepG2 cells. Transfection with hSulf-1 cDNA and/or
stat3
siRNA inhibited cell proliferation and motility, concurrent with G
0
/G
1
and G
2
/M phase cell cycle arrest and apoptosis. Overall, the results of the current study suggested that hSulf-1 functions as a negative regulator of proliferation and migration and as a positive regulator of apoptosis in hepatocellular carcinoma, at least partly via the downregulation of
stat3
signaling.
...
PMID:hSulf-1 inhibits cell proliferation and migration and promotes apoptosis by suppressing stat3 signaling in hepatocellular carcinoma. 2494 51
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.
...
PMID:The extracellular sulfatase SULF2 promotes liver tumorigenesis by stimulating assembly of a promoter-looping GLI1-STAT3 transcriptional complex. 3198 46
