CRSP8 plays an important role in recruiting mediators to genes through direct interaction with various DNA-bound transactivators. In this study, we uncovered the unique function of CRSP8 in suppressing thyroid cancer differentiation and promoting thyroid cancer progression via targeting IKKα signaling. CRSP8 was highly expressed in human thyroid cancer cells and tissues, especially in anaplastic thyroid cancer (ATC). Knockdown of CRSP8 suppressed cell growth, migration, invasion, stemness, and induced apoptosis and differentiation in ATC cells, while its overexpression displayed opposite effects in differentiated thyroid cancer (DTC) cells. Mechanistically, CRSP8 downregulated IKKα expression by binding to the IKKα promoter region (−257 to −143) to negatively regulate its transcription. Knockdown or overexpression of IKKα significantly reversed the expression changes of the differentiation and EMT-related markers and cell growth changes mediated by CRSP8 knockdown or overexpression in ATC or DTC cells. The in vivo study also validated that CRSP8 knockdown inhibited the growth of thyroid cancer by upregulating IKKα signaling in a mouse model of human ATC. Furthermore, we found that CRSP8 regulated the sensitivity of thyroid cancer cells to chemotherapeutics, including cisplatin and epirubicin. Collectively, our results demonstrated that CRSP8 functioned as a modulator of IKKα signaling and a suppressor of thyroid cancer differentiation, suggesting a potential therapeutic strategy for ATC by targeting CRSP8/IKKα pathway.

CRSP8 通过与各种 DNA 结合的反式激活因子直接相互作用，在为基因招募介质方面发挥重要作用。在这项研究中，我们揭示了 CRSP8 通过靶向 IKKα 信号传导抑制甲状腺癌分化和促进甲状腺癌进展的独特功能。CRSP8在人甲状腺癌细胞和组织中高度表达，特别是在甲状腺未分化癌（ATC）中。CRSP8 的敲低抑制了 ATC 细胞的细胞生长、迁移、侵袭、干性，并诱导了细胞凋亡和分化，而其过表达在分化的甲状腺癌 (DTC) 细胞中表现出相反的作用。从机制上讲，CRSP8 通过与 IKKα 启动子区域（-257 至 -143）结合来负调控 IKKα 的转录，从而下调 IKKα 的表达。IKKα的敲低或过表达显着逆转了ATC或DTC细胞中CRSP8敲低或过表达介导的分化和EMT相关标志物的表达变化以及细胞生长变化。体内研究还验证了 CRSP8 敲低通过在人类 ATC 小鼠模型中上调 IKKα 信号传导来抑制甲状腺癌的生长。此外，我们发现 CRSP8 调节甲状腺癌细胞对化疗药物的敏感性，包括顺铂和表柔比星。总的来说，我们的结果表明 CRSP8 可作为 IKKα 信号传导的调节剂和甲状腺癌分化的抑制因子，这表明通过靶向 CRSP8/IKKα 通路来治疗 ATC 的潜在治疗策略。