Multiomics analyses reveal DARS1-AS1 /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 DARS1-AS1 –controlled posttranscriptional circuitry that promoted the malignant properties of GBM cells/GSCs. Depleting DARS1-AS1 inhibited the proliferation of GBM cells/GSCs and self-renewal of GSCs, prolonging survival in orthotopic GBM models. DARS1-AS1 depletion also impaired the homologous recombination (HR)–mediated double-strand break (DSB) repair and enhanced the radiosensitivity of GBM cells/GSCs. Mechanistically, DARS1-AS1 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 G 1 -S transition, including E2F1 and CCND1. DARS1-AS1 /YBX1 also stabilized the mRNA of FOXM1 , a master transcription factor regulating GSC self-renewal and DSB repair. Our findings suggest DARS1-AS1 /YBX1 axis as a potential therapeutic target for sensitizing GBM to radiation/HR deficiency–targeted therapy.