Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance

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

doi:10.1126/sciadv.adf3984

Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance

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 ChenFrederick F. Lang, Jian Hu, Yiwen Chen

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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.

Original language	English (US)
Article number	eadf3984
Journal	Science Advances
Volume	9
Issue number	31
DOIs	https://doi.org/10.1126/sciadv.adf3984
State	Published - Aug 2023

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Zheng, C., Wei, Y., Zhang, Q., Sun, M., Wang, Y., Hou, J., Zhang, P., Lv, X., Su, D., Jiang, Y., Gumin, J., Sahni, N., Hu, B., Wang, W., Chen, X., McGrail, D. J., Zhang, C., Huang, S., Xu, H., ... Chen, Y. (2023). Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance. Science Advances, 9(31), Article eadf3984. https://doi.org/10.1126/sciadv.adf3984

Zheng, C , Wei, Y, Zhang, Q, Sun, M, Wang, Y, Hou, J, Zhang, P, Lv, X, Su, D, Jiang, Y, Gumin, J, Sahni, N, Hu, B, Wang, W, Chen, X, McGrail, DJ, Zhang, C, Huang, S, Xu, H , Chen, J , Lang, FF , Hu, J & Chen, Y 2023, 'Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance', Science Advances, vol. 9, no. 31, eadf3984. https://doi.org/10.1126/sciadv.adf3984

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title = "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 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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2023 The Authors, some rights reserved.",

year = "2023",

month = aug,

doi = "10.1126/sciadv.adf3984",

language = "English (US)",

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T1 - Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance

AU - Zheng, Caishang

AU - Wei, Yanjun

AU - Zhang, Qiang

AU - Sun, Ming

AU - Wang, Yunfei

AU - Hou, Jiakai

AU - Zhang, Peng

AU - Lv, Xiangdong

AU - Su, Dan

AU - Jiang, Yujie

AU - Gumin, Joy

AU - Sahni, Nidhi

AU - Hu, Baoli

AU - Wang, Wenyi

AU - Chen, Xi

AU - McGrail, Daniel J.

AU - Zhang, Chaolin

AU - Huang, Suyun

AU - Xu, Han

AU - Chen, Junjie

AU - Lang, Frederick F.

AU - Hu, Jian

AU - Chen, Yiwen

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

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Multiomics analyses reveal DARS1-AS1/YBX1–controlled posttranscriptional circuits promoting glioblastoma tumorigenesis/radioresistance

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