The stress-induced lincRNAJUNIis a critical factor for cancer cell survival whose interactome is a prognostic signature in clear cell renal cell carcinoma

Abstract

AbstractCancer cells rely on adaptive mechanisms to survive the multiple stressors they encounter, including replication stress, toxic metabolic products and exposure to genotoxic drugs. Understanding the factors involved in these stress responses is crucial for developing effective treatments. Here, we describe a previously unstudied long non-coding RNA (lncRNA),JUNI(JUN-DT,LINC01135), which is regulated by MAPK and responsive to stress.JUNIpositively regulates the expression of its neighboring geneJUN, a key transducer of signals that regulate multiple transcriptional outputs. Our findings reveal that silencingJUNIsensitizes cancer cells to chemotherapeutic drugs or UV radiation, and that its prolonged silencing leads to cell death regardless of stress exposure, highlighting the pro-survival importance ofJUNI.We identified 57 proteins that interact withJUNIand found that the activity of one of them, the MAPK phosphatase and inhibitor DUSP14, is inhibited byJUNI. This effect results in c-Jun induction following exposure of cancer cells to UV radiation and promotes cellular survival. AlthoughJUNIregulates c-Jun and its downstream targets, the pro-survival effects in cells not exposed to stress are only partially dependent on c-Jun regulation.JUNIexpression levels significantly correlate with patients survival across 11 different types of cancer. Interestingly, the correlation of DUSP14 expression levels with patients survival in nine of these tumors is coherently inverse, indicating contradicting effects that are relevant not only for c-Jun induction and cellular survival but also in human cancer. Notably, we observed particularly significant antagonistic correlations in clear cell renal cell carcinoma (ccRCC) (p=5.7E-05 forJUNIand p=2.9E- 05 for Dusp14). In fact, the expression levels of 76% ofJUNI-interacting proteins predict the prognosis of ccRCC patients significantly. Furthermore, a combined hazard ratio calculation demonstrates that this gene combination serves as a highly specific prognostic signature for ccRCC. Overall, our findings reveal a new important factor in stress signaling and cellular survival that is involved in ccRCC.