SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma
SULF1 inhibits tumor growth and potentiates the effects of histone deacetylase inhibitors in hepatocellular carcinoma
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DOI：
10.1053/j.gastro.2006.02.056
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发表时间：
2006-06-01
期刊：
影响因子：
29.4
通讯作者：
Roberts, Lewis R.
中科院分区：
文献类型：
--
作者：
Lai, Jin-Ping;Yu, Chunrong;Roberts, Lewis R.
背景与目的：肝细胞癌是全球第三大癌症死亡原因。改善晚期肝癌的治疗是当务之急。新近发现的人硫酸酯酶1酶(SULF1)在体外可使肝癌细胞表面硫酸乙酰肝素糖胺聚糖脱硫化，并下调细胞生长信号。在研究SULF1的表观遗传调控时，我们发现SULF1上调了肝癌细胞中组蛋白H4的乙酰化。组蛋白脱乙酰酶(HDAC)抑制剂通过核小体组蛋白的乙酰化重新编程细胞基因表达，促进细胞生长停滞和凋亡。因此，它们是一种很有前途的癌症治疗方法。方法：通过观察SULF1的表达对肝癌细胞和经HDAC抑制剂处理的移植瘤的影响，探讨SULF1表达与HDAC抑制剂作用的相互作用。结果：(1)强制表达SULF1显著延缓了裸鼠移植瘤HuH7和Hep313的生长。(2)SULF1通过调节细胞内HDAC和组蛋白乙酰转移酶活性，促进组蛋白H4乙酰化。(3)SULF1可增强HDAC抑制剂Apicidin和Scriptaid诱导的细胞凋亡。(4)SULF1可增强HDAC抑制剂对肿瘤生长、迁移和血管生成的抑制作用。我们还证明，用shRNA敲除SULF1构建了上调AKT和ERK的磷酸化，并减弱了蜂毒诱导的细胞凋亡。在HuH7和Hep313移植瘤中，证实了SULF1与Apicidin的相互作用。结论：SULF1促进组蛋白H4乙酰化，增强HDAC抑制剂的作用，抑制肝癌的发生。
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 Hep313 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 Hep313 xenografts. Conclusions: These results show that SULF1 promotes histone H4 acetylation, potentiates the effects of HDAC inhibitors, and inhibits HCC tumorigenesis.