title: SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma.
abstract: OBJECTIVE
  Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. Improved treatments for advanced HCC are urgently needed. The recently identified human sulfatase 1 enzyme (SULF1) desulfates cell surface heparan sulfate glycosaminoglycans and down-regulates cell growth signaling in HCC cells in vitro. While investigating the epigenetic regulation of SULF1, we discovered that histone H4 acetylation is up-regulated by SULF1 in HCC cells. Histone deacetylase (HDAC) inhibitors reprogram cellular gene expression through the acetylation of nucleosomal histones and promote cell growth arrest and apoptosis. Hence, they are a promising modality for cancer treatment.
  
  
  METHODS
  To explore the interaction between SULF1 expression and HDAC inhibitor action, we examined the effects of SULF1 expression on HCC cells and xenografts treated with HDAC inhibitors.
  
  
  RESULTS
  (1) Forced expression of SULF1 significantly delayed the growth of Huh7 and Hep3B xenografts in nude mice in vivo. (2) SULF1 increased histone H4 acetylation by modulation of cellular HDAC and histone acetyltransferase activities. (3) SULF1 enhanced the induction of apoptosis by the HDAC inhibitors apicidin and scriptaid. (4) SULF1 enhanced the inhibition of tumor growth, migration, and angiogenesis by HDAC inhibitors. We also demonstrate that knockdown of SULF1 with shRNA constructs up-regulates phosphorylation of AKT and Erk and attenuates apicidin-induced apoptosis. The interaction between SULF1 and apicidin was confirmed in vivo in Huh7 and Hep3B xenografts.
  
  
  CONCLUSIONS
  These results show that SULF1 promotes histone H4 acetylation, potentiates the effects of HDAC inhibitors, and inhibits HCC tumorigenesis.
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Lai
authors.forename: Chunrong
authors.initials: C
authors.lastname: Yu
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.forename: Ileana
authors.initials: I
authors.lastname: Aderca
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Garvey
authors.forename: Linda M
authors.initials: LM
authors.lastname: Murphy
authors.forename: Megan M
authors.initials: MM
authors.lastname: Garrity-Park
authors.forename: Viji
authors.initials: V
authors.lastname: Shridhar
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000107:Acetylation; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology; D020169:Caspases / Q000032:analysis; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000201:enzymology*; D002470:Cell Survival; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D012334:RNA, Neoplasm / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D013429:Sulfatases / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012334:RNA, Neoplasm; D013429:Sulfatases; D020169:Caspases; D006655:Histone Deacetylases