Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity
Histone deacetylase SIRT6 regulates chemosensitivity in liver cancer cells via modulation of FOXO3 activity
复制标题
组蛋白脱乙酰酶 SIRT6 通过调节 FOXO3 活性调节肝癌细胞的化疗敏感性
DOI：
10.3892/or.2018.6770
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发表时间：
2018-12-01
期刊：
影响因子：
4.2
通讯作者：
Tian, Xue-Fei
中科院分区：
文献类型：
--
作者：
Hu, Jia-Qing;Deng, Fang;Tian, Xue-Fei
肝癌是世界范围内癌症相关死亡的主要原因，其发病率正在增加。近几十年来，人们已经做出了相当大的努力来改善肝癌的诊断和治疗。晚期肝癌常表现出对化疗的不良反应，由于获得性耐药和肿瘤复发，预后不良。了解负责化疗药物诱导的细胞死亡的精确分子机制可能会发现新的治疗靶点并改善肝癌治疗。在本研究中，证明了在对阿霉素（最常用于肝癌治疗的化合物）的响应中，组蛋白脱乙酰酶sirtuin 6（SIRT 6）被特异性下调。这使得叉头盒O3（FOXO 3）上调，易位到细胞核中，并增加其靶基因p27和Bim的表达，从而进一步诱导细胞凋亡。SIRT 6的过表达，而不是酶失活的突变体，防止FOXO 3易位到细胞核和阿霉素诱导的细胞死亡。SIRT 6与FOXO 3相互作用，这种相互作用增加FOXO 3泛素化并降低其稳定性。最后，确定SIRT 6在防止阿霉素诱导的细胞死亡中的作用需要FOXO 3。SIRT 6的过表达不能阻止FOXO 3敲低细胞中阿霉素诱导的细胞死亡。因此，可以得出结论，SIRT 6通过调节FOXO 3活性在确定阿霉素诱导的细胞死亡中起着重要作用。SIRT 6和/或FOXO 3的治疗靶向可能为肝癌的治疗提供新的策略。
Liver cancer is the leading cause of cancer-related mortality worldwide and its incidence is increasing. Considerable effort has been made in recent decades to improve the diagnosis and treatment of liver cancer. Advanced liver cancer often exhibits a poor response to chemotherapy and poor prognosis due to acquired chemoresistance and tumor recurrence. Understanding the precise molecular mechanisms that are responsible for chemotherapeutic drug-induced cell death could potentially identify novel therapeutic targets and improve liver cancer treatment. In the present study, it was demonstrated that in response to doxorubicin, the most frequently used chemical compound for liver cancer treatment, histone deacetylase sirtuin 6 (SIRT6) is specifically downregulated. This enables forkhead box O3 (FOXO3) upregulation, translocation into the nucleus and increased expression of its target genes p27 and Bim, which further induce apoptosis. Overexpression of SIRT6, but not enzyme-inactivated mutants, prevents FOXO3 translocation into the nucleus and doxorubicin-induced cell death. SIRT6 interacts with FOXO3 and this interaction increases FOXO3 ubiquitination and decreases its stability. Finally, it was identified that the effect of SIRT6 in preventing doxorubicin-induced cell death requires FOXO3. Overexpression of SIRT6 could not prevent doxorubicin-induced cell death in FOXO3-knockdown cells. Therefore, it was concluded that SIRT6 plays a central role in determining doxorubicin-induced cell death via modulation of FOXO3 activity. Therapeutic targeting of SIRT6 and/or FOXO3 may offer novel strategies for treatment of liver cancer.