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

• Published in: Communications biology 2022-08, Vol.5 (1), p.822-822, Article 822
• Main Authors: Yang, Liuqing, Lin, Kequan, Zhu, Lin, Wang, Huili, Teng, Shuaishuai, Huang, Lijun, Zhou, Shiyi, Zhang, Guanbin, Lu, Zhi John, Wang, Dong
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/2; 13/31; 14/19; 38/47; 631/337/384; 631/67/395; Antisense RNA; Apoptosis; Aspartate-tRNA ligase; Biology; Biomedical and Life Sciences; Cancer; Cell death; Cell growth; Cell proliferation; Cellular stress response; eIF-2 kinase; Kinases; Life Sciences; Medical prognosis; Non-coding RNA; Phosphorylation; Prognosis; Protein kinase R; tRNA; Tumor cell lines; Tumors
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03778-y

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. A loss-of-function screen reveals a role for lncRNA DARS-AS1 in promoting cancer cell proliferation and further experiments shows DARS-AS1 regulates the PACT-PKR pathway, overall suggesting it as a potential target for cancer therapy and prognosis.