Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells
Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells
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DOI：
10.1038/sj.onc.1211000
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发表时间：
2008-05-01
期刊：
影响因子：
8
通讯作者：
Lee, M-O
中科院分区：
文献类型：
--
作者：
Yoo, Y-G;Na, T-Y;Lee, M-O
转移相关蛋白1（metastasis-associated protein 1，MTA 1）的表达水平与多种肿瘤的生长和转移密切相关。虽然在肝细胞癌（HCC）中观察到MTA 1表达水平增加，但含有组蛋白脱乙酰酶（HDAC）的MTA 1复合物在B型肝炎病毒（HBV）相关肝癌发生中的作用尚未研究。在此，我们证明HBx在转录水平强烈诱导MTA 1和HDAC 1基因的表达。在存在HBx的情况下，MTA 1和HDAC 1/2在体内与缺氧诱导因子-1 α（HIF-1 α）物理相关，通过短干扰RNA（siRNA）敲低MTA 1可消除这种相关性。HBx诱导HIF-1 α的氧依赖性降解结构域的脱乙酰化，这伴随着脯氨酰羟化酶和von Hippel-Lindau肿瘤抑制因子从HIF-1 α的解离。这些结果表明HBx诱导的去乙酰化对于HIF-1 α的蛋白酶体降解是重要的。此外，我们观察到，在HBx转基因小鼠的肝脏中，MTA 1和HDAC 1的蛋白水平增加。此外，在12例HBV相关的HCC标本中，有10例HCC中HDAC 1的表达高于邻近的非肿瘤性结节。总之，我们的数据表明HBx和MTA 1/HDAC复合物在稳定HIF-1 α方面存在积极的相互作用，HIF-1 α可能在HBV相关HCC的血管生成和转移中发挥关键作用。
Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 alpha (HIF-1 alpha) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1 alpha, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1 alpha. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1 alpha. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1 alpha, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.