Characterization of the HDAC1 Complex That Regulates the Sensitivity of Cancer Cells to Oxidative Stress
Characterization of the HDAC1 Complex That Regulates the Sensitivity of Cancer Cells to Oxidative Stress
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DOI：
10.1158/0008-5472.can-08-4368
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发表时间：
2009-04-15
期刊：
影响因子：
11.2
通讯作者：
Takahashi, Masahide
中科院分区：
文献类型：
--
作者：
Kato, Takuya;Shimono, Yohei;Takahashi, Masahide
组蛋白去乙酰化酶（HDAC）通过调节细胞增殖、分化和存活参与癌的发生。HDAC的抑制剂在与其他抗癌药物组合时在癌症治疗中表现出深刻的协同作用。然而，这种协同作用的分子机制尚未完全理解。在这里，我们表明HDAC 1通过负调节硫氧还蛋白结合蛋白2（TBP-2）的表达来增加癌细胞对氧化应激的抵抗力。我们发现HDAC 1向TBP-2启动子的募集是由RET指蛋白（RFP;也称为TRIM 27）和三聚体转录因子NF-Y组成的蛋白复合物介导的。因此，RNA干扰介导的RFP耗竭导致蛋白质复合物的破坏和癌细胞对顺铂（一种有效的氧化应激诱导剂）的敏感性显著增加。此外，RFP的高水平表达与人类结肠癌中TBP-2的下调相关，并与不良的临床结局相关。这些发现揭示了HDAC 1的多种促癌活性，并将RFP确定为使癌细胞对抗癌药物产生耐药性的关键调节因子。[Cancer Res 2009;69（8）：3597-604]
Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to theTBP-2promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference–mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs. [Cancer Res 2009;69(8):3597–604]