Department of Periodontics, Stomatological Hospital, Southern Medical University, Guangzhou, China.
Oral Dis. 2022 Nov;28(8):2139-2148. doi: 10.1111/odi.13860. Epub 2021 May 4.
Treatment of oral squamous cell carcinoma remains a challenge due to a high incidence of treatment resistance, which is followed by tumor recrudescence and metastasis to the lymph nodes. Thus, it is important to explore novel inhibitors of OSCC. Here, we aimed to identify drugs that may cooperate with histone deacetylase inhibitors to reverse the EMT, inhibit EMT and cell migration and invasion, and contribute to therapeutic efficacy. We found that treatment with 4sc-202 potently reversed the EMT and thereby inhibited cell migration and invasion in vitro, in part by inducing expression of the FoxO1 tumor-suppressor gene. Furthermore, 4sc-202 also synergized with Ink-128 to inhibit tumor migration and invasion in vitro. Mechanistically, 4sc-202 induced FoxO1 expression, whereas Ink-128 promoted nuclear translocation of FoxO1. Our findings indicated that FoxO1 might reverse the EMT by interacting with Twist1 in OSCC. In conclusion, we identified an effective combination therapy involving class I histone deacetylase and mammalian target of rapamycin complex 1/2 inhibition that effectively blocked the EMT of tumor cells by upregulating FoxO1 expression to inhibit Twist1 transcription. These data have implications for developing new targets for early diagnosis and treatment of OSCC.
由于治疗抵抗的发生率较高，口腔鳞状细胞癌的治疗仍然是一个挑战，随后肿瘤复发并转移到淋巴结。因此，探索口腔鳞状细胞癌的新型抑制剂很重要。在这里，我们旨在确定可能与组蛋白去乙酰化酶抑制剂协同作用的药物，以逆转 EMT、抑制 EMT 和细胞迁移和侵袭，并有助于治疗效果。我们发现，用 4sc-202 治疗可有效逆转 EMT，从而在体外抑制细胞迁移和侵袭，部分原因是诱导 FoxO1 肿瘤抑制基因的表达。此外，4sc-202 还与 Ink-128 协同抑制体外肿瘤迁移和侵袭。从机制上讲，4sc-202 诱导 FoxO1 表达，而 Ink-128 促进 FoxO1 的核易位。我们的研究结果表明，FoxO1 可能通过与口腔鳞状细胞癌中的 Twist1 相互作用来逆转 EMT。总之，我们确定了一种有效的联合治疗方法，涉及 I 类组蛋白去乙酰化酶和哺乳动物雷帕霉素靶蛋白复合物 1/2 的抑制，通过上调 FoxO1 表达抑制 Twist1 转录，有效地阻断肿瘤细胞的 EMT。这些数据为开发口腔鳞状细胞癌早期诊断和治疗的新靶点提供了依据。
