Long non-coding RNA DARS-AS1 promotes tumor progression by directly suppressing PACT-mediated cellular stress

Abstract

Cancer cells evolve various mechanisms to overcome cellular stresses and maintain progression. Protein kinase R (PKR) and its protein activator (PACT) are the initial responders in monitoring diverse stress signals and lead to inhibition of cell proliferation and cell apoptosis in consequence. However, the regulation of PACT-PKR pathway in cancer cells remains largely unknown. Herein, we identify that the long non-coding RNA (lncRNA) aspartyl-tRNA synthetase antisense RNA 1 (DARS-AS1) is directly involved in the inhibition of the PACT-PKR pathway and promotes the proliferation of cancer cells. Using large-scale CRISPRi functional screening of 971 cancer-associated lncRNAs, we find that DARS-AS1 is associated with significantly enhanced proliferation of cancer cells. Accordingly, knocking down DARS-AS1 inhibits cell proliferation of multiple cancer cell lines and promotes cancer cell apoptosis in vitro and significantly reduces tumor growth in vivo. Mechanistically, DARS-AS1 directly binds to the activator domain of PACT and prevents PACT-PKR interaction, thereby decreasing PKR activation, eIF2α phosphorylation and inhibiting apoptotic cell death. Clinically, DARS-AS1 is broadly expressed across multiple cancers and the increased expression of this lncRNA indicates poor prognosis. This study elucidates the lncRNA DARS-AS1 directed cancer-specific modulation of the PACT-PKR pathway and provides another target for cancer prognosis and therapeutic treatment.

DARS-AS1: A Vital Oncogenic LncRNA Regulator with Potential for Cancer Prognosis and Therapy

“…ensembl.org/Homo_sapiens/Gene/Summary?g = ENSG00000231890; r = 2:135985124-136022593). As an antisense lncRNA, DARS-AS1 has emerged as a recognized oncogenic entity, implicated in a wide array of cancer types as supported by extensive research publications [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51], as depicted in Figure 1. These encompass cancers originating from various organ systems, including the digestive, urinary, respiratory, female reproductive, hematological, and neurological systems, among others.…”

“…When acting as a protein decoy, in colorectal cancer 46 , DARS-AS1 directly bound to PACT. This interaction inhibited the association between PACT and PKR, preventing the phosphorylation of the PKR downstream substrate eIF2α, ultimately inhibiting apoptotic cell death.…”

“…This interaction inhibited the association between PACT and PKR, preventing the phosphorylation of the PKR downstream substrate eIF2α, ultimately inhibiting apoptotic cell death. In breast cancer and HCC 46 , DARS-AS1 promoted cancer cell proliferation and inhibited apoptosis by inhibiting the function of PACT. In myeloma 44 , DARS-AS1 exerts its function by binding RNA-binding motif protein 39 (RBM39), which impedes the interaction between RBM39 and its E3 ubiquitin ligase RNF147 and prevents RBM39 from degradation.…”

“…In hepatocellular carcinoma 35 , DARS-AS1 up-regulates CKAP2 by binding to miR-3200-5p, thereby activating the FAK-ERK pathway and promoting HCC proliferation and metastasis, and DARS-AS1 is also reported to promote HCC cell proliferation and inhibits apoptosis through inhibiting the function of PACT 46 . In lung adenocarcinoma 42 , it was found that DARS-AS1 significantly enhances the malignant properties of LUAD cells.…”

“…In breast cancer, DARS-AS1 promote the TNBC tumorigenesis by activation of the NF-κB/STAT3 signaling pathway 40 , and increased the resistance of TNBC cells to doxorubicin by promote TGF-β/Smad3 signaling pathway-induced autophagy 41 . In addition, DARS-AS1 inhibits breast cancer cell proliferation, which is, at least partially, through repressing PACT-mediated PKR activation 46 . In cervical cancer, DARS-AS1 exhibits pro-tumorigenic effects by activating the Notch pathway 33 , and cGMP-PKG pathway 37 , exacerbating the tumorigenesis of cervical cancer.…”