核PKM2与前mRNA中折叠G-四链体结合并揭示其基因调控作用

Nuclear PKM2 binds pre-mRNA at folded G-quadruplexes and reveals their gene regulatory role

MOLECULAR CELL

影响因子:16.6

分区:生物学1区 Top / 生化与分子生物学1区细胞生物学1区

发表日期:2024 Oct 03

作者: Dimitrios G Anastasakis, Maria Apostolidi, Khalid A Garman, Ahsan H Polash, Mubarak I Umar, Qingcai Meng, Jérémy Scutenaire, Jordan E Jarvis, Xiantao Wang, Astrid D Haase, Isaac Brownell, Jesse Rinehart, Markus Hafner

DOI: 10.1016/j.molcel.2024.07.025

摘要

核内代谢酶PKM2的定位在多种癌症中普遍观察到。我们发现核PKM2是一种非典型的RNA结合蛋白（RBP），能特异性结合前体mRNA（pre-mRNA）中的折叠RNA G-四链体（rG4）结构。PKM2在rG4上的结合阻止了HNRNPF等抑制性RBP的结合，促进含rG4的pre-mRNA（“rG4ome”）的表达。在上皮-间充质转化（EMT）过程中，rG4ome表达上调，并且不同癌症类型中rG4丰度与患者生存率呈负相关。通过阻止PKM2在核内的积累，可以抑制三阴性乳腺癌细胞中的rG4ome，减少癌细胞的迁移和侵袭。在体外和异种移植小鼠模型中，调控rG4的折叠状态影响肿瘤进展中基因表达的平衡。我们的数据表明，RBPs控制的折叠与非折叠rG4的平衡影响肿瘤进展中的基因表达。由Elsevier公司发表。

Abstract

Nuclear localization of the metabolic enzyme PKM2 is widely observed in various cancer types. We identify nuclear PKM2 as a non-canonical RNA-binding protein (RBP) that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs (pre-mRNAs). PKM2 occupancy at rG4s prevents the binding of repressive RBPs, such as HNRNPF, and promotes the expression of rG4-containing pre-mRNAs (the "rG4ome"). We observe an upregulation of the rG4ome during epithelial-to-mesenchymal transition and a negative correlation of rG4 abundance with patient survival in different cancer types. By preventing the nuclear accumulation of PKM2, we could repress the rG4ome in triple-negative breast cancer cells and reduce migration and invasion of cancer cells in vitro and in xenograft mouse models. Our data suggest that the balance of folded and unfolded rG4s controlled by RBPs impacts gene expression during tumor progression.Published by Elsevier Inc.