Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2
Combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the initiation and recurrence of oral squamous cell carcinomas by repressing SOX2
复制标题
I 类组蛋白脱乙酰酶和 mTORC1/C2 联合抑制通过抑制 SOX2 抑制口腔鳞状细胞癌的发生和复发
DOI：
10.1016/j.canlet.2019.04.010
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Xia, Juan
中科院分区：
文献类型：
--
作者：
Liang, Xueyi;Deng, Miao;Xia, Juan
由于缺乏有效的早期治疗策略和高复发率，口腔鳞状细胞癌（OSCC）的治疗仍然是一个挑战。在这里，我们发现，4SC-202（一种新型选择性 I 类 HDAC 抑制剂）和 INK128（一种选择性 mTORC1/C2 抑制剂）联合治疗在抑制 OSCC 中的细胞生长、球体形成能力、皮下肿瘤形成和 ALDH1 (+) 癌症干细胞 (CSC) 方面表现出协同作用。在 4NQO 诱导的大鼠模型中，联合治疗显着抑制了 OSCC 的发生。此外，SOX2上调与OSCC患者的晚期和转移性肿瘤相关，并导致OSCC细胞的耐药特性。 SOX2 过度表达减弱了联合治疗对细胞活力和 ALDH1 CSC 的抑制作用。此外，联合治疗可以有效克服化疗耐药性并抑制体外和体内复发性口腔鳞癌的生长。从机制上讲，4SC-202 和 INK128 分别通过 miR-429/miR-1181 介导的 mRNA 降解和阻止帽依赖性 mRNA 翻译来抑制 SOX2 表达。这些结果表明，I 类组蛋白脱乙酰酶和 mTORC1/C2 联合抑制可通过抑制 SOX2 来抑制 OSCC 的癌变和复发。
Treatment of oral squamous cell carcinoma (OSCC) remains a challenge because of the lack of effective early treatment strategies and high incidence of relapse. Here, we showed that combined 4SC-202 (a novel selective class I HDAC inhibitor) and INK128 (a selective mTORC1/C2 inhibitor) treatment exhibited synergistic effects on inhibiting cell growth, sphere-forming ability, subcutaneous tumor formation and ALDH1 (+) cancer stem cells (CSCs) in OSCC. The initiation of OSCC was significantly inhibited by combined treatment in 4NQO-induced rat model. In addition, upregulated SOX2 was associated with advanced and metastatic tumors in OSCC patients and was responsible for the drug-resistance property of OSCC cells. The inhibitory effect of combined treatment on cell viability and ALDH1 CSCs were attenuated by SOX2 verexpression. Furthermore, combined treatment can effectively overcome chemoresistance and inhibit the growth of recurrent OSCC in vitro and in vivo. Mechanistically, 4SC-202 and INK128 repressed SOX2 expression through miR-429/miR-1181-mediated mRNA degradation and preventing cap-dependent mRNA translation, respectively. These results suggest that combined class I histone deacetylase and mTORC1/C2 inhibition suppresses the carcinogenesis and recurrence of OSCC by repressing SOX2.