SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma.
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.
Lai
Jin-Ping
JP
Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
Yu
Chunrong
C
Moser
Catherine D
CD
Aderca
Ileana
I
Han
Tao
T
Garvey
Thomas D
TD
Murphy
Linda M
LM
Garrity-Park
Megan M
MM
Shridhar
Viji
V
Adjei
Alex A
AA
Roberts
Lewis R
LR
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
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D012334:RNA, Neoplasm; D013429:Sulfatases; D020169:Caspases; D006655:Histone Deacetylases