H19 Is a PERK-Regulated Long Non-Coding RNA That Fine-Tunes UPR Signalling and Inhibits Endoplasmic Reticulum Stress-Induced Cell Death

Abstract The endoplasmic reticulum (ER) responds to stimuli that disrupt its homeostasis by activating a signalling network known as unfolded protein response (UPR), that restores cellular balance and determines cell fate through three key sensors: IRE1, PERK, and ATF6. Emerging evidence suggests that the UPR regulates the expression of numerous long non-coding RNAs (lncRNAs), which play critical roles in modulating stress responses. Here we show that expression of lncRNA H19 is downregulated in response to ER stress in breast cancer cells. Using genetic and pharmacological approaches, we demonstrate that this downregulation is primarily mediated by the PERK arm of the UPR. Specifically, knockdown or chemical inhibition of PERK compromised the ER stress-mediated H19 repression, while PERK activation significantly reduced H19 expression. H19 overexpression promotes the optimal activation of ATF6 and PERK pathways, while it attenuates the signalling by IRE1-XBP1 axis of the UPR. Bioinformatic analyses across multiple breast cancer cohorts revealed that high H19 expression correlates with poor prognosis, particularly in basal-like subtypes. Furthermore, in triple-negative breast cancer (TNBC) cells, H19 was found to provide resistance to ER stress-induced apoptosis. Collectively, our findings establish H19 as a key regulatory node in the UPR network, where PERK-mediated repression of H19 shapes cellular outcomes under ER stress. These insights position H19 as a potential therapeutic target in breast cancer, especially in aggressive subtypes such as TNBC.