Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation
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DOI：
10.1038/onc.2009.306
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发表时间：
2010-01-07
期刊：
影响因子：
8
通讯作者：
Fusco, A.
中科院分区：
文献类型：
--
作者：
Borbone, E.;Berlingieri, M. T.;Fusco, A.
甲状腺未分化癌（ATC）被认为是最具侵袭性的恶性肿瘤之一，预后较差，并且对常规化疗和放疗难以治疗。据报道，癌症中组蛋白脱乙酰酶 (HDAC) 活性发生改变，从而促进了 HDAC 抑制剂的开发，其抗肿瘤作用已在实体瘤和血液恶性肿瘤中得到证实。然而，它们的肿瘤选择性的分子基础尚不清楚。为了找到治疗 ATC 的创新疗法，我们研究了脱乙酰酶抑制剂对甲状腺肿瘤发生模型的影响。我们发现，与正常细胞或良性肿瘤相比，HDAC 1 和 2 在 ATC 中过度表达，并且 HDAC 抑制剂在完全转化的甲状腺细胞中选择性诱导细胞凋亡。我们的结果表明，这些现象是由 HDAC 抑制剂的一种新作用介导的，该抑制剂通过影响泛素依赖性途径来减少肿瘤坏死因子相关的凋亡诱导配体蛋白降解。事实上，HDAC 和蛋白酶体抑制剂的联合治疗会导致协同细胞凋亡。这些结果强烈鼓励脱乙酰酶-蛋白酶体抑制剂组合用于治疗 ATC 的临床前应用。
Anaplastic thyroid carcinoma (ATC) is considered one of the most aggressive malignancies, having a poor prognosis and being refractory to conventional chemotherapy and radiotherapy. Alteration in histone deacetylase (HDAC) activity has been reported in cancer, thus encouraging the development of HDAC inhibitors, whose antitumor action has been shown in both solid and hematological malignancies. However, the molecular basis for their tumor selectivity is unknown. To find an innovative therapy for the treatment of ATCs, we studied the effects of deacetylase inhibitors on thyroid tumorigenesis models. We show that HDACs 1 and 2 are overexpressed in ATCs compared with normal cells or benign tumors and that HDAC inhibitors induce apoptosis selectively in the fully transformed thyroid cells. Our results indicate that these phenomena are mediated by a novel action of HDAC inhibitors that reduces tumor necrosis factor-related apoptosis-inducing ligand protein degradation by affecting the ubiquitin-dependent pathway. Indeed, the combined treatment with HDAC and proteasome inhibitors results in synergistic apoptosis. These results strongly encourage the preclinical application of the combination deacetylase-proteasome inhibitors for the treatment of ATC.