Cancer cell stemness results in the occurrence and progression of tumors and Oct4 (octamer-binding transcription factor) has been confirmed to be a critical contributor and marker of cancer cell stemness. Here, we aimed to explore the underlying mechanisms contributing to Oct4 protein stability, which is necessary for thyroid cancer (TC) cell stemness. We indicated that carboxy terminus of HSP70-interacting protein (CHIP) protein was lowly expressed in TC tissues and cells, and positively correlated with the overall survival of TC patients. By analyzing the co-expression network in TC tissues, we found that CHIP and Oct4 expression exhibited a negative correlation. Functional experiments showed that CHIP knockdown promoted the stemness of TC cells, while CHIP overexpression reduced the stemness of TC spheroids formed by TC cells, in which CHIP expression was significantly decreased. Furthermore, CHIP had no effect on TC cell viability. Mechanistic studies revealed that CHIP directly interacted with Oct4 protein and induced Oct4 ubiquitination, whereas a catalytic CHIP mutant (H260Q) did not. And CHIP regulated the stemness of TC cells in an Oct4-dependent manner. Overall, this work indicates that the CHIP/Oct4 axis is essential for TC cell stemness.

中文翻译：

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HSP70 相互作用蛋白 (CHIP) 的羧基末端通过降低 OCT4 蛋白稳定性减弱甲状腺癌细胞的干性

癌细胞干性导致肿瘤的发生和发展，Oct4（八聚体结合转录因子）已被证实是癌细胞干性的关键贡献者和标志物。在这里，我们旨在探索有助于 Oct4 蛋白稳定性的潜在机制，这对于甲状腺癌 (TC) 细胞干细胞至关重要。我们表明HSP70相互作用蛋白（CHIP）蛋白的羧基末端在TC组织和细胞中低表达，并且与TC患者的总体存活率呈正相关。通过分析TC组织中的共表达网络，我们发现CHIP和Oct4表达呈负相关。功能实验表明，CHIP 敲低促进了 TC 细胞的干性，而 CHIP 过表达降低了 TC 细胞形成的 TC 球体的干性，其中 CHIP 表达显着降低。此外，CHIP 对 TC 细胞活力没有影响。机理研究表明，CHIP 直接与 Oct4 蛋白相互作用并诱导 Oct4 泛素化，而催化 CHIP 突变体（H260Q）则没有。CHIP 以 Oct4 依赖性方式调节 TC 细胞的干性。总体而言，这项工作表明 CHIP/Oct4 轴对于 TC 细胞干性至关重要。