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

The endoplasmic reticulum (ER) responds to stimuli that disrupts 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: inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), and protein kinase RNA-like ER kinase (PERK). Emerging evidence suggests that UPR regulates the expression of numerous long non-coding RNAs (lncRNAs), which play critical roles in maintaining ER homeostasis. Here we show that expression of lncRNA H19 is downregulated in response to ER stress in (MCF7, T47D and 293T) cells. Using genetic and pharmacological approaches, we demonstrate that H19 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. Furthermore, in triple-negative breast cancer (TNBC) cells MDA-MB-231, ectopic H19 provided resistance to ER stress-induced apoptosis. Bioinformatic analyses across multiple breast cancer cohorts revealed that high H19 expression was associated with poor prognosis, particularly in basal-like subtypes. Collectively, our findings show that H19 is downregulated during UPR in a PERK-dependent manner, where H19 in turn modulates UPR signalling and cell fate during conditions of ER stress.