Xu Debin, Yu Jichun, Yang Yuting, Du Yunyan, Lu Hongcheng, Zhang Shouhua, Feng Qian, Yu Yi, Hao Liang, Shao Jun, Chen Leifeng
Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Nanchang, 330008, China.
Department of Intensive Care Unit, First Affiliated Hospital of Nanchang University, No. 17, Yongwai Main Street, Nanchang, 330006, China.
Cell Biosci. 2023 Feb 21;13(1):36. doi: 10.1186/s13578-023-00987-8.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, frequently accompanied by metastasis and aerobic glycolysis. Cancer cells adjust their metabolism by modulating the PKM alternative splicing and facilitating PKM2 isoform expression. Therefore, identifying factors and mechanisms that control PKM alternative splicing is significant for overcoming the current challenges in ATC treatment.
In this study, the expression of RBX1 was largely enhanced in the ATC tissues. Our clinical tests suggested that high RBX1 expression was significantly related to poor survival. The functional analysis indicated that RBX1 facilitated the metastasis of ATC cells by enhancing the Warburg effect, and PKM2 played a key role in RBX1-mediated aerobic glycolysis. Furthermore, we confirmed that RBX1 regulates PKM alternative splicing and promotes the PKM2-mediated Warburg effect in ATC cells. Moreover, ATC cell migration and aerobic glycolysis induced by RBX1-mediated PKM alternative splicing are dependent on the destruction of the SMAR1/HDAC6 complex. RBX1, as an E3 ubiquitin ligase, degrades SMAR1 in ATC through the ubiquitin-proteasome pathway.
Overall, our study identified the mechanism underlying the regulation of PKM alternative splicing in ATC cells for the first time and provides evidence about the effect of RBX1 on cellular adaptation to metabolic stress.
间变性甲状腺癌（ATC）是最具侵袭性的恶性肿瘤之一，常伴有转移及有氧糖酵解。癌细胞通过调节丙酮酸激酶M2（PKM）可变剪接及促进PKM2亚型表达来调整其代谢。因此，确定控制PKM可变剪接的因素和机制对于克服当前ATC治疗面临的挑战具有重要意义。
在本研究中，RBX1在ATC组织中的表达大幅增强。我们的临床试验表明，高RBX1表达与较差的生存率显著相关。功能分析表明，RBX1通过增强瓦伯格效应促进ATC细胞转移，且PKM2在RBX1介导的有氧糖酵解中起关键作用。此外，我们证实RBX1调节ATC细胞中PKM可变剪接并促进PKM2介导的瓦伯格效应。而且，RBX1介导的PKM可变剪接诱导的ATC细胞迁移及有氧糖酵解依赖于SMAR1/HDAC6复合物的破坏。RBX1作为一种E3泛素连接酶，通过泛素-蛋白酶体途径在ATC中降解SMAR1。
总体而言，我们的研究首次确定了ATC细胞中PKM可变剪接调控的潜在机制，并提供了RBX1对细胞适应代谢应激影响的证据。
