Anaplastic thyroid cancer (ATC) is one of the most aggressive and virulent solid tumors. The ubiquitin proteasome system presents in all eukaryotic cells and is essential for cellular homeostasis. While its underlying role in ATC remains largely unclear. TRIM11 is an E3 ubiquitin ligase and has been reported to act as an oncogene in several human cancers. The present study aims to reveal the oncogenic function of TRIM11 in ATC. Western blot was used to measure the protein expression of TRIM11 and YAP, while the YAP target genes were measured by real-time PCR. CCK8 assay was used to detect cell viability; wound-healing assay and transwell assay were used to measure the migration ability of ATC. The xeno-graft tumor model was used for in vivo study. Immuno-precipitation assay was used to detect the interaction domain between YAP and TRIM11. And the ubiquitin-based Immuno-precipitation assays were used to detect the specific ubiquitination manner happened on YAP. TRIM11 depletion significantly decreases cell proliferation and migration capabilities of ATC cells, and elevates cell sensitivity to chemotherapy, which effect could be further rescued by YAP overexpression. TRIM11 depletion decreases YAP protein level and YAP/TEAD target genes, such as CTGF, ANKRD1 and CYR61 in ATC. Indicating that TRIM11 is a regulator of Hippo signaling pathway. Immuno-precipitation assay shows that the RING domain of TRIM11 is essential for the interaction with WW domain of YAP. Further mechanistic analysis suggests that TRIM11 promotes the mono-ubiquitination of YAP, thus prolongs its protein half. Furthermore, TRIM11 promoter analysis revealed that SOX13 activates TRIM11 transcription by binding to the promoter of TRIM11. In summary, our study describes the oncogenic function of TRIM11 in ATC, which acts as a post-translational modulating factor of Hippo pathway. Targeting TRIM11 may be a potential therapeutic method for ATC treatment.

中文翻译：

---

SOX13/TRIM11/YAP轴促进间变性甲状腺癌的增殖、迁移和化疗耐药

甲状腺未分化癌 (ATC) 是最具侵袭性和毒性最强的实体瘤之一。泛素蛋白酶体系统存在于所有真核细胞中，对细胞稳态至关重要。虽然它在 ATC 中的潜在作用仍不清楚。TRIM11 是一种 E3 泛素连接酶，据报道在几种人类癌症中充当癌基因。本研究旨在揭示 TRIM11 在 ATC 中的致癌功能。Western印迹用于测量TRIM11和YAP的蛋白质表达，而YAP靶基因通过实时PCR测量。CCK8法检测细胞活力；伤口愈合试验和transwell试验用于测量ATC的迁移能力。异种移植肿瘤模型用于体内学习。免疫沉淀法用于检测 YAP 和 TRIM11 之间的相互作用域。并且使用基于泛素的免疫沉淀测定来检测YAP上发生的特定泛素化方式。TRIM11 耗竭显着降低 ATC 细胞的细胞增殖和迁移能力，并提高细胞对化疗的敏感性，这种作用可以通过 YAP 过表达进一步挽救。TRIM11 消耗降低了 YAP 蛋白水平和 YAP/TEAD 靶基因，例如 ATC 中的 CTGF、ANKRD1 和 CYR61。表明TRIM11是Hippo信号通路的调节因子。免疫沉淀分析表明，TRIM11 的 RING 结构域对于与 YAP 的 WW 结构域的相互作用是必不可少的。进一步的机制分析表明，TRIM11 促进 YAP 的单泛素化，从而延长其蛋白质的一半。此外，TRIM11 启动子分析显示 SOX13 通过与 TRIM11 的启动子结合来激活 TRIM11 转录。总之，我们的研究描述了 TRIM11 在 ATC 中的致癌功能，它作为 Hippo 通路的翻译后调节因子。靶向 TRIM11 可能是 ATC 治疗的一种潜在治疗方法。