PDF(Pubmed)
Abstract：
Cancer cells employ adaptive mechanisms to survive various stressors, including genotoxic drugs. Understanding the factors promoting survival is crucial for developing effective treatments. In this study, we unveil a previously unexplored long non-coding RNA, JUNI (JUN-DT, LINC01135), which is upregulated by genotoxic drugs through the activation of stress-activated MAPKs, JNK, and p38 and consequently exerts positive control over the expression of its adjacent gene product c-Jun, a well-known oncoprotein, which transduces signals to multiple transcriptional outputs. JUNI regulates cellular migration and has a crucial role in conferring cellular resistance to chemotherapeutic drugs or UV radiation. Depletion of JUNI markedly increases the sensitivity of cultured cells and spheroids to chemotherapeutic agents. We identified 57 proteins interacting with JUNI. The activity of one of them the MAPK phosphatase and inhibitor, DUSP14, is counteracted by JUNI, thereby, facilitating efficient JNK phosphorylation and c-Jun induction when cells are exposed to UV radiation. The antagonistic interplay with DUSP14 contributes not only to c-Jun induction but also augments the survival of UV-exposed cells. In summary, we introduce JUNI as a novel stress-inducible regulator of c-Jun, positioning it as a potential target for enhancing the sensitivity of cancer cells to chemotherapy.
摘要：
癌细胞采用适应性机制来生存各种压力源，包括基因毒性药物.了解促进生存的因素对于开发有效的治疗方法至关重要。在这项研究中,我们揭示了一个以前未被探索的长的非编码RNA，JUNI(JUN-DT,LINC01135),它通过激活应激激活的MAPK被基因毒性药物上调，JNK,和p38，因此对其相邻基因产物c-Jun的表达施加阳性控制，一种众所周知的癌蛋白，它将信号转换为多个转录输出。JUNI调节细胞迁移并在赋予细胞对化疗药物或紫外线辐射的抗性方面具有关键作用。JUNI的消耗显着增加了培养细胞和球体对化学治疗剂的敏感性。我们鉴定了57种与JUNI相互作用的蛋白质。其中一种MAPK磷酸酶和抑制剂的活性，DUSP14，由JUNI抵消，因此，当细胞暴露于紫外线辐射时，促进有效的JNK磷酸化和c-Jun诱导。与DUSP14的拮抗相互作用不仅有助于c-Jun诱导，而且还增加了紫外线照射细胞的存活。总之,我们引入JUNI作为一种新型的c-Jun应激诱导调节剂，将其定位为增强癌细胞对化疗敏感性的潜在靶标。
