Multiomics analyses reveal <i>DARS1-AS1</i>/YBX1-controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance.

Abstract

The glioblastoma (GBM) stem cell-like cells (GSCs) are critical for tumorigenesis/therapeutic resistance of GBM. Mounting evidence supports tumor-promoting function of long noncoding RNAs (lncRNAs), but their role in GSCs remains poorly understood. By combining CRISPRi screen with orthogonal multiomics approaches, we identified a lncRNA <i>DARS1-AS1</i>-controlled posttranscriptional circuitry that promoted the malignant properties of GBM cells/GSCs. Depleting <i>DARS1-AS1</i> inhibited the proliferation of GBM cells/GSCs and self-renewal of GSCs, prolonging survival in orthotopic GBM models. <i>DARS1-AS1</i> depletion also impaired the homologous recombination (HR)-mediated double-strand break (DSB) repair and enhanced the radiosensitivity of GBM cells/GSCs. Mechanistically, <i>DARS1-AS1</i> interacted with YBX1 to promote target mRNA binding and stabilization, forming a mixed transcriptional/posttranscriptional feed-forward loop to up-regulate expression of the key regulators of G₁-S transition, including E2F1 and CCND1. <i>DARS1-AS1</i>/YBX1 also stabilized the mRNA of <i>FOXM1</i>, a master transcription factor regulating GSC self-renewal and DSB repair. Our findings suggest <i>DARS1-AS1</i>/YBX1 axis as a potential therapeutic target for sensitizing GBM to radiation/HR deficiency-targeted therapy.