Interdisciplinary Cluster for Applied Genoproteomics (GIGA), University of Liege, CHU, Sart-Tilman, Liège, Belgium.
Laboratory of Medical Chemistry, University of Liege, CHU, Sart-Tilman, Liège, Belgium.
Nat Commun. 2020 Mar 9;11(1):1270. doi: 10.1038/s41467-020-15003-7.
Prolonged cell survival occurs through the expression of specific protein isoforms generated by alternate splicing of mRNA precursors in cancer cells. How alternate splicing regulates tumor development and resistance to targeted therapies in cancer remain poorly understood. Here we show that RNF113A, whose loss-of-function causes the X-linked trichothiodystrophy, is overexpressed in lung cancer and protects from Cisplatin-dependent cell death. RNF113A is a RNA-binding protein which regulates the splicing of multiple candidates involved in cell survival. RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis due to enhanced SAT1 expression, and increased production of ROS due to altered Noxa1 expression. RNF113A deficiency circumvents the resistance to Cisplatin and to BCL-2 inhibitors through the destabilization of MCL-1, which thus defines spliceosome inhibitors as a therapeutic approach to treat tumors showing acquired resistance to specific drugs due to MCL-1 stabilization.
延长的细胞存活是通过在癌细胞中 mRNA 前体的可变剪接表达特定的蛋白质异构体来实现的。可变剪接如何调节肿瘤的发展和对癌症靶向治疗的耐药性仍知之甚少。在这里，我们表明，RNF113A 的功能丧失会导致 X 连锁的先天性角化不良，在肺癌中过度表达，并能抵抗顺铂依赖性细胞死亡。RNF113A 是一种 RNA 结合蛋白，可调节多种与细胞存活相关的候选物的剪接。RNF113A 缺陷通过多种机制在 DNA 损伤时触发细胞死亡，包括通过破坏生存蛋白 MCL-1 诱导的细胞凋亡、由于 SAT1 表达增强而导致的铁死亡，以及由于 Noxa1 表达改变而导致的 ROS 产生增加。RNF113A 缺陷通过破坏 MCL-1 来规避顺铂和 BCL-2 抑制剂的耐药性，因此，剪接体抑制剂被定义为治疗因 MCL-1 稳定而对特定药物产生获得性耐药的肿瘤的一种治疗方法。
