核出口信号
异质核核糖核蛋白
基因敲除
核孔
信使核糖核酸
癌症研究
细胞生物学
RNA结合蛋白
核糖核酸
化学
癌症
生物
核糖核蛋白
基因
生物化学
核心
遗传学
作者
Ting Jin,Liping Yang,C.S. Chang,Haojun Luo,Rui Wang,Yubi Gan,Yan Sun,Yuetong Guo,Rui Tang,Shan-Chun Chen,Die Meng,Peijin Dai,Manran Liu
标识
DOI:10.1002/advs.202307639
摘要
Abstract Regulating nuclear export precisely is essential for maintaining mRNA homeostasis and impacts tumor progression. However, the mechanisms governing nuclear mRNA export remain poorly elucidated. Herein, it is revealed that the enhanced hypoxic long no‐ncoding RNA (lncRNA prostate cancer associated transcript 6 (PCAT6) in breast cancer (BC) promotes the nuclear export of m6A‐modified mRNAs, bolstering breast cancer stem cells (BCSCs) stemness and doxorubicin resistance. Clinically, hypoxic PCAT6 correlates with malignant BC features and poor prognosis. Mechanically, PCAT6 functions as a scaffold between interferon‐stimulated gene 15 (ISG15) and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2B1), leading to ISGylation of hnRNPA2B1, thus protecting hnRNPA2B1 from ubiquitination‐mediated proteasomal degradation. Interestingly, as an m6A reader, hnRNPA2B1 selectively mediates m6A‐tagged mRNAs nuclear export via the Aly/REF export factor (ALYREF)/ nuclear RNA export factor 1 (NXF1) complex, which promotes stemness‐related genes expression. HnRNPA2B1 knockdown or mRNA export inhibition can result in the retention of nuclear m6A‐tagged mRNA associated with stemness maintenance, which suppresses BCSCs self‐renewal and effectively improves the efficacy of doxorubicin therapy. These findings demonstrate the pivotal role of m6A‐modified mRNA nuclear export in BC progression, highlighting that the inhibition of m6A‐tagged mRNA and its nuclear export is a potential therapeutic strategy for the amelioration of cancer chemotherapy.
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