PDF(Pubmed)
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.
摘要：
精确调节核输出对于维持mRNA稳态和影响肿瘤进展至关重要。然而,控制核mRNA输出的机制仍未阐明。在这里，揭示了乳腺癌（BC）中增强的缺氧长非编码RNA（lncRNA前列腺癌相关转录本6（PCAT6）促进m6A修饰的mRNA的核输出，支持乳腺癌干细胞（BCSCs）干性和阿霉素抗性。临床上,低氧PCAT6与恶性BC特征和不良预后相关。机械上,PCAT6充当干扰素刺激基因15（ISG15）和异质核核糖核蛋白A2/B1（hnRNPA2B1）之间的支架，导致hnRNPA2B1的ISG化，从而保护hnRNPA2B1免受泛素化介导的蛋白酶体降解。有趣的是,作为M6A阅读器，hnRNPA2B1通过Aly/REF出口因子（ALYREF）/核RNA出口因子1（NXF1）复合物选择性介导m6A标记的mRNA核出口，这促进了干性相关基因的表达。HnRNPA2B1敲低或mRNA输出抑制可导致保留与干性维持相关的核m6A标记的mRNA，抑制BCSCs自我更新,有效提高阿霉素治疗的疗效。这些发现证明了m6A修饰的mRNA核输出在BC进展中的关键作用，强调抑制m6A标记的mRNA及其核输出是改善癌症化疗的潜在治疗策略。
