HnRNPA2B1 ISGylation Regulates m6A-Tagged mRNA Selective Export via ALYREF/NXF1 Complex to Foster Breast Cancer Development
作者全名："Jin, Ting; Yang, Liping; Chang, Chao; Luo, Haojun; Wang, Rui; Gan, Yubi; Sun, Yan; Guo, Yuetong; Tang, Rui; Chen, Shanchun; Meng, Die; Dai, Peijin; Liu, Manran"
作者地址："[Jin, Ting; Chang, Chao; Wang, Rui; Gan, Yubi; Guo, Yuetong; Tang, Rui; Chen, Shanchun; Meng, Die; Dai, Peijin; Liu, Manran] Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China; [Yang, Liping] Chongqing Med Univ, Affiliated Hosp 2, Dept Lab Med, Chongqing 400010, Peoples R China; [Luo, Haojun] Chongqing Med Univ, Affiliated Hosp 2, Dept Breast & Thyroid Surg, Chongqing 400010, Peoples R China; [Sun, Yan] Chongqing Med Univ, Basic Med Sch, Dept Cell Biol & Med Genet, Chongqing 400016, Peoples R China"
通信作者："Jin, T; Liu, MR (通讯作者)，Chongqing Med Univ, Key Lab Lab Med Diagnost, Chinese Minist Educ, Chongqing 400016, Peoples R China."
来源：ADVANCED SCIENCE
ESI学科分类：PHYSICS
WOS号：WOS:001203158000001
JCR分区：Q1
影响因子：14.3
年份：2024
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：ISG15; m6A mRNA; mRNA export
摘要："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. Illustration of the underlying mechanism by which hypoxic PCAT6-mediated hnRNPA2B1 ISGylation promotes BC progression. This process culminates in the stabilization of HnRNPA2B1, enhancing the FGFR1 mRNA nuclear export, which is subjected to N6-methyladenosine (m6A) modifications. image"
基金机构："National Natural Science Foundation of China [NSFC81874199, NSFC82173155]; Outstanding Professorship Program of Chongqing Medical University [2019-R10005]; Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission [CXQT20012]; Outstanding Postgraduate Fund of Chongqing Medical University [BJRC202113]"
基金资助正文："This work was supported in part by the National Natural Science Foundation of China (NSFC81874199 and NSFC82173155), the Outstanding Professorship Program of Chongqing Medical University (2019-R10005), and by the Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission (No. CXQT20012) to M.L. And also supported by the outstanding Postgraduate Fund of Chongqing Medical University (BJRC202113) for T.J."
