Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression
Histone Deacetylase (HDAC) 10 Suppresses Cervical Cancer Metastasis through Inhibition of Matrix Metalloproteinase (MMP) 2 and 9 Expression
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组蛋白脱乙酰酶 (HDAC) 10 通过抑制基质金属蛋白酶 (MMP) 2 和 9 的表达来抑制宫颈癌转移。
DOI：
10.1074/jbc.m113.498758
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发表时间：
2013-09-27
影响因子：
4.8
通讯作者：
Kang, Jiuhong
中科院分区：
文献类型：
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作者：
Song, Chenlin;Zhu, Songcheng;Kang, Jiuhong
组蛋白去乙酰化酶（HDAC）的异常表达与肿瘤发生有关。一些HDAC抑制剂被广泛认为是有前途的抗癌治疗剂。开发HDAC抑制剂作为高度安全和有效的抗癌治疗剂的主要障碍是我们目前对不同HDAC在各种癌症类型中的贡献的了解仍然很少。在这里，我们报告的HDAC 10的表达水平显着降低，在患者表现出淋巴结转移的人宫颈鳞状细胞癌相比，在没有淋巴结转移的患者。HDAC 10在宫颈癌细胞中的强制表达显著抑制细胞的运动性和体外侵袭性以及体内转移。从机制上讲，HDAC 10抑制基质金属蛋白酶（MMP）2和9基因的表达，这些基因已知对癌细胞侵袭和转移至关重要。在分子水平上，HDAC 10与MMP 2和MMP-9启动子区域结合，降低组蛋白乙酰化水平，并抑制RNA聚合酶II与这些区域的结合。此外，缺乏组蛋白脱乙酰酶活性的HDAC 10突变体未能模拟全长蛋白的功能。这些结果确定了HDAC 10在抑制宫颈癌转移中的关键作用，强调了开发亚型特异性HDAC抑制剂用于治疗某些癌症类型如宫颈鳞状细胞癌的重要性。
Aberrant expression of histone deacetylases (HDACs) is associated with carcinogenesis. Some HDAC inhibitors are widely considered as promising anticancer therapeutics. A major obstacle for development of HDAC inhibitors as highly safe and effective anticancer therapeutics is that our current knowledge on the contributions of different HDACs in various cancer types remains scant. Here we report that the expression level of HDAC10 was significantly lower in patients exhibiting lymph node metastasis compared with that in patients lacking lymph node metastasis in human cervical squamous cell carcinoma. Forced expression of HDAC10 in cervical cancer cells significantly inhibited cell motility and invasiveness in vitro and metastasis in vivo. Mechanistically, HDAC10 suppresses expression of matrix metalloproteinase (MMP) 2 and 9 genes, which are known to be critical for cancer cell invasion and metastasis. At the molecular level, HDAC10 binds to MMP2 and -9 promoter regions, reduces the histone acetylation level, and inhibits the binding of RNA polymerase II to these regions. Furthermore, an HDAC10 mutant lacking histone deacetylase activity failed to mimic the functions of full-length protein. These results identify a critical role of HDAC10 in suppression of cervical cancer metastasis, underscoring the importance of developing isoform-specific HDAC inhibitors for treatment of certain cancer types such as cervical squamous cell carcinoma.