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Learn MoreThe expression of the extracellular sulfatase, SULF2, has been strongly associated with increased hepatocellular carcinoma (HCC) tumor growth and poorer patient survival. However, to date, the molecular mechanisms underlying this phenomenon remain in part unclear. To address this issue, we developed a transgenic mouse overexpressing Sulf2 in hepatocytes under the control of the transthyretin promoter. In this mouse model Sulf2 overexpression potentiated DEN-induced HCC. Further analysis demonstrated a central role for the zinc finger transcription factor Gli1 as a mediator of Sulf2 during HCC development. The cross of the Sulf2 transgenic with Gli1 knockout mice showed that the inactivation of this transcription factor impaired Sulf2-induced HCC. Transcriptomic analysis revealed a Stat3 gene signatures associated with Sulf2 overexpression. Interestingly, Gli1 knockout abrogates Sulf2-induction of several Stat3 target genes including Socs2/3, Pim1 and Flt4. Human orthologues were similarly regulated by SULF2 and dependent on intact GLI1 and STAT3 function in human HCC cells. SULF2 overexpression not only resulted in GLI1 and STAT3 interaction, but also promoted enrichment of GLI1 and STAT3 at consensus sites at the target gene promoters. Interestingly, GLI1 was found to be enriched at select STAT3 consensus sites with SULF2 overexpression and vice versa. siRNA-mediated knockdown of STAT3 or GLI1 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. Thus, these findings define a novel mechanism by which SULF2 drives HCC and highlights the role of GLI1-STAT3 transcriptional complex as an effector of this sulfatase. SOURCE: Asha Nair (nair.asha@mayo.edu) - Mayo Clinic
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