SULF1 Inhibits Tumor Growth and Potentiates the Effects of Histone Deacetylase Inhibitors in Hepatocellular Carcinoma

Jin Ping Lai, Chunrong Yu, Catherine D. Moser, Ileana Aderca, Tao Han, Thomas D. Garvey, Linda M. Murphy, Megan M. Garrity-Park, Vijayalakshmi Shridhar, Alex Adjei, Lewis Rowland Roberts

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2130-2144
Number of pages15
JournalGastroenterology
Volume130
Issue number7
DOIs
StatePublished - Jul 2006

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Sulfatases
Histone Deacetylase Inhibitors
Hepatocellular Carcinoma
Enzymes
Growth
Neoplasms
Acetylation
Histones
Heterografts
Apoptosis
Histone Acetyltransferases
Enzyme Induction
Histone Deacetylases
Heparitin Sulfate
Glycosaminoglycans
Epigenomics
Nude Mice
Small Interfering RNA
Cause of Death
Carcinogenesis

ASJC Scopus subject areas

  • Gastroenterology

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SULF1 Inhibits Tumor Growth and Potentiates the Effects of Histone Deacetylase Inhibitors in Hepatocellular Carcinoma. / Lai, Jin Ping; Yu, Chunrong; Moser, Catherine D.; Aderca, Ileana; Han, Tao; Garvey, Thomas D.; Murphy, Linda M.; Garrity-Park, Megan M.; Shridhar, Vijayalakshmi; Adjei, Alex; Roberts, Lewis Rowland.

In: Gastroenterology, Vol. 130, No. 7, 07.2006, p. 2130-2144.

Research output: Contribution to journalArticle

Lai, Jin Ping ; Yu, Chunrong ; Moser, Catherine D. ; Aderca, Ileana ; Han, Tao ; Garvey, Thomas D. ; Murphy, Linda M. ; Garrity-Park, Megan M. ; Shridhar, Vijayalakshmi ; Adjei, Alex ; Roberts, Lewis Rowland. / SULF1 Inhibits Tumor Growth and Potentiates the Effects of Histone Deacetylase Inhibitors in Hepatocellular Carcinoma. In: Gastroenterology. 2006 ; Vol. 130, No. 7. pp. 2130-2144.
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abstract = "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.",
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T1 - SULF1 Inhibits Tumor Growth and Potentiates the Effects of Histone Deacetylase Inhibitors in Hepatocellular Carcinoma

AU - Lai, Jin Ping

AU - Yu, Chunrong

AU - Moser, Catherine D.

AU - Aderca, Ileana

AU - Han, Tao

AU - Garvey, Thomas D.

AU - Murphy, Linda M.

AU - Garrity-Park, Megan M.

AU - Shridhar, Vijayalakshmi

AU - Adjei, Alex

AU - Roberts, Lewis Rowland

PY - 2006/7

Y1 - 2006/7

N2 - 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.

AB - 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.

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U2 - 10.1053/j.gastro.2006.02.056

DO - 10.1053/j.gastro.2006.02.056

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