SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma.

BACKGROUND & AIMS 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.

[1]  Danila Coradini,et al.  Histone deacetylase inhibitors for treatment of hepatocellular carcinoma , 2005, Acta Pharmacologica Sinica.

[2]  K. Reddy,et al.  Distinct mechanisms mediate the initial and sustained phases of cell migration in epidermal growth factor receptor-overexpressing cells. , 2003, Molecular cancer research : MCR.

[3]  A. Manning,et al.  Sodium butyrate induces apoptosis in human colonic tumour cell lines in a p53‐independent pathway: Implications for the possible role of dietary fibre in the prevention of large‐bowel cancer , 1993, International journal of cancer.

[4]  David I. Smith,et al.  HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma , 2004, Oncogene.

[5]  P. Atadja,et al.  Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia. , 2004, Haematologica.

[6]  Dipali Sharma,et al.  A Novel Histone Deacetylase Inhibitor, Scriptaid, Enhances Expression of Functional Estrogen Receptor α (ER) in ER negative human breast cancer cells in combination with 5-aza 2′-deoxycytidine , 2003, Breast Cancer Research and Treatment.

[7]  K. Glaser,et al.  Gene expression profiling of multiple histone deacetylase (HDAC) inhibitors: defining a common gene set produced by HDAC inhibition in T24 and MDA carcinoma cell lines. , 2003, Molecular cancer therapeutics.

[8]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[9]  L. Schwartz,et al.  Phase I clinical trial of histone deacetylase inhibitor: suberoylanilide hydroxamic acid administered intravenously. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[10]  D. Schuppan,et al.  The histone-deacetylase inhibitor Trichostatin A blocks proliferation and triggers apoptotic programs in hepatoma cells. , 2002, Journal of hepatology.

[11]  E. Seto,et al.  Histone deacetylases and cancer , 2007, Oncogene.

[12]  정회경,et al.  Apicidin potentiates the imatinib-induced apoptosis of Bcr–Abl-positive human leukaemia cells by enhancing the activation of mitochondria-dependent caspase cascades , 2004 .

[13]  P. Munster,et al.  Sequence‐specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid , 2004, Journal of cellular biochemistry.

[14]  K. McManus,et al.  Quantitative Analysis of CBP- and P300-Induced Histone Acetylations In Vivo Using Native Chromatin , 2003, Molecular and Cellular Biology.

[15]  J. Trepel,et al.  Transcriptional activation of p21(WAF1/CIP1) by apicidin, a novel histone deacetylase inhibitor. , 2001, Biochemical and biophysical research communications.

[16]  J. Cheong,et al.  Apicidin potentiates the imatinib‐induced apoptosis of Bcr–Abl‐positive human leukaemia cells by enhancing the activation of mitochondria‐dependent caspase cascades , 2004, British journal of haematology.

[17]  M. Mandal,et al.  Butyric acid induces apoptosis by up-regulating Bax expression via stimulation of the c-Jun N-terminal kinase/activation protein-1 pathway in human colon cancer cells. , 2001, Gastroenterology.

[18]  Jorge A. Almenara,et al.  The histone deacetylase inhibitor MS-275 promotes differentiation or apoptosis in human leukemia cells through a process regulated by generation of reactive oxygen species and induction of p21CIP1/WAF1 1. , 2003, Cancer research.

[19]  C. Monneret,et al.  Histone deacetylase inhibitors. , 2005, European journal of medicinal chemistry.

[20]  Jorge A. Almenara,et al.  Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. , 2003, Molecular cancer therapeutics.

[21]  M. Minemura,et al.  Sodium butyrate enhances Fas-mediated apoptosis of human hepatoma cells. , 2004, Journal of hepatology.

[22]  M. Mandal,et al.  Bcl-2 expression regulates sodium butyrate-induced apoptosis in human MCF-7 breast cancer cells. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[23]  M. Gregor,et al.  Apoptosis on hepatoma cells but not on primary hepatocytes by histone deacetylase inhibitors valproate and ITF2357. , 2005, Journal of hepatology.

[24]  C. Sung,et al.  Induction and superinduction of growth arrest and DNA damage gene 45 (GADD45) alpha and beta messenger RNAs by histone deacetylase inhibitors trichostatin A (TSA) and butyrate in SW620 human colon carcinoma cells. , 2002, Cancer letters.

[25]  Yin-Won Lee,et al.  Apicidin is a histone deacetylase inhibitor with anti-invasive and anti-angiogenic potentials. , 2004, Biochemical and biophysical research communications.

[26]  David I. Smith,et al.  Loss of HSulf-1 Up-regulates Heparin-binding Growth Factor Signaling in Cancer* , 2003, Journal of Biological Chemistry.

[27]  David I. Smith,et al.  hSulf1 Sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling. , 2004, Gastroenterology.

[28]  G. Otterson,et al.  The interaction of histone deacetylase inhibitors and DNA methyltransferase inhibitors in the treatment of human cancer cells. , 2003, Current medicinal chemistry. Anti-cancer agents.

[29]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[30]  E. Mekada,et al.  HB-EGF promotes epithelial cell migration in eyelid development , 2005, Development.

[31]  D. Kessler,et al.  QSulf1, a heparan sulfate 6-O-endosulfatase, inhibits fibroblast growth factor signaling in mesoderm induction and angiogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Teufel,et al.  Histone deacetylase inhibition by valproic acid down-regulates c-FLIP/CASH and sensitizes hepatoma cells towards CD95- and TRAIL receptor-mediated apoptosis and chemotherapy. , 2006, Oncology reports.

[33]  P. Dennis,et al.  Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. , 2002, Molecular cancer therapeutics.

[34]  David I. Smith,et al.  Identification of underexpressed genes in early- and late-stage primary ovarian tumors by suppression subtraction hybridization. , 2002, Cancer research.

[35]  G. Gores,et al.  Hepatocellular carcinoma: molecular pathways and new therapeutic targets. , 2005, Seminars in liver disease.

[36]  D. Paik,et al.  The Histone Deacetylase Inhibitor MS-275 Interacts Synergistically with Fludarabine to Induce Apoptosis in Human Leukemia Cells , 2004, Cancer Research.

[37]  J. Licht,et al.  Histone Acetyltransferase Activity of p300 Is Required for Transcriptional Repression by the Promyelocytic Leukemia Zinc Finger Protein , 2004, Molecular and Cellular Biology.

[38]  D. Schuppan,et al.  The histone-deacetylase inhibitor SAHA potentiates proapoptotic effects of 5-fluorouracil and irinotecan in hepatoma cells , 2005, Journal of Cancer Research and Clinical Oncology.

[39]  Michael D. Abràmoff,et al.  Image processing with ImageJ , 2004 .