Multiomics Analyses Reveal DARS1-AS1/YBX1-Controlled Posttranscriptional Circuits Promoting Glioblastoma Tumorigenesis/Radioresistance

Authors

Caishang Zheng
Yanjun Wei
Qiang Zhang
Ming Sun
Yunfei Wang
Jiakai Hou
Peng Zhang
Xiangdong Lv
Dan Su
Yujie Jiang
Joy Gumin
Nidhi Sahni
Baoli Hu
Wenyi Wang
Xi Chen
Daniel J McGrail
Chaolin Zhang
Suyun Huang
Han Xu
Junjie Chen
Frederick F Lang
Jian Hu
Yiwen Chen

Publication Date

8-4-2023

Journal

Science Advances

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 G1-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.

Keywords

Humans, Brain Neoplasms, Carcinogenesis, Cell Line, Tumor, Cell Proliferation, Cell Transformation, Neoplastic, Gene Expression Regulation, Neoplastic, Glioblastoma, Multiomics, RNA, Long Noncoding, Y-Box-Binding Protein 1

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Supplementary Materials

PMID: 37540752