A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance

Nan Sun; Qun Chen; Hao Chen; Penggang Sun; Yuxiang Liu; Dan Song; Daohan Yu; Pandeng Wang; Yu Song; Jie Qin; Kaifu Tian; Junzhe Zhong; Wenbin Ma; Hanwen Xuan; Da Qian; Ye Yuan; Tongzheng Chen; Xin Wang; Chuanlu Jiang; Jinquan Cai; Xiangqi Meng

doi:10.1093/neuonc/noae272

A novel nuclear RNA HSD52 scaffolding NONO/SFPQ complex modulates DNA damage repair to facilitate temozolomide resistance

Neuro Oncol. 2024 Dec 14:noae272. doi: 10.1093/neuonc/noae272. Online ahead of print.

Authors

Nan Sun¹, Qun Chen², Hao Chen^{1

3}, Penggang Sun¹, Yuxiang Liu¹, Dan Song^{1

3}, Daohan Yu^{1

3}, Pandeng Wang^{1

3}, Yu Song¹, Jie Qin^{1

3}, Kaifu Tian¹, Junzhe Zhong^{1

3}, Wenbin Ma¹, Hanwen Xuan¹, Da Qian⁴, Ye Yuan⁵, Tongzheng Chen¹, Xin Wang^{1

3}, Chuanlu Jiang^{1

6}, Jinquan Cai¹, Xiangqi Meng¹

Affiliations

¹ Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University; Harbin, China.
² Department of Neurosurgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
³ Future Medical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin, China.
⁴ Department of Burn and Plastic Surgery-Hand Surgery, Changshu Hospital Affiliated to Soochow University, Changshu No.1 People's Hospital, Changshu, China.
⁵ Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶ The Sixth Affiliated Hospital of Harbin Medical University; Harbin, China.

PMID: 39673809
DOI: 10.1093/neuonc/noae272

Abstract

Background: Temozolomide (TMZ) is used in the treatment of glioblastoma (GBM). However, the primary obstacle remains the emergence of TMZ chemotherapy resistance. NONO and SFPQ are multifunctional nuclear proteins involved in genome stability and gene regulation. However, the specific role of NONO and SFPQ in TMZ resistance of GBM remains to be explored.

Methods: RIP-chip and RNA microarray of TMZ-resistant and parental cells were performed for the gain of HSD52. The effects of HSD52 on TMZ resistance were investigated through in vitro assays, intracranial xenograft and GBM organoid models. The underlying mechanisms were explored by DNA methylation chip, RIP, RNA pulldown assays, among others. GBM clinical samples were rolled in to investigate the clinical significance of HSD52.

Results: We identified a novel non-coding RNA, HSD52, that was highly expressed in TMZ-resistant GBM and facilitated the interaction between NONO and SFPQ. H3 ubiquitination attenuation and reduced DNMT1 recruitment increased HSD52 transcription via DNA hypo-methylation. HSD52 formed an RNA duplex with UFL1 mRNA, thereby promoting NONO/SFPQ complex binding to UFL1 mRNA and enhancing its stability, and then contributed to TMZ resistance through activating ATM signaling pathway. In vivo xenograft and GBM organoid models showed significant repression in tumor growth after HSD52 knockout with TMZ treatment. In GBM clinical samples, HSD52 was responsible for the malignant progression and TMZ resistance.

Conclusions: Our results revealed that HSD52 could serve as a promising therapeutic target to overcome TMZ resistance, improving the clinical efficacy of TMZ chemotherapy in GBM.

Keywords: DNA damage repair; Glioblastoma; HSD52; NONO/SFPQ complex; Temozolomide resistance.

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