PRMT1 inhibitor MS023 suppresses RNA splicing to sensitize small cell lung cancer to DNA damaging agents

IF 4.8 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia Pub Date : 2025-05-23 DOI:10.1016/j.neo.2025.101176

Mansi K. Aparnathi , Sami Ul Haq , Jonathan St-Germain , Kevin C.J. Nixon , Joseph Walton , Lifang Song , Safa Majeed , Parasvi S. Patel , Ratheesh Subramaniam , Vivek Philip , Richard Marcellus , Dalia Barsyte-Lovejoy , Rima Al-Awar , Razqallah Hakem , Cheryl H. Arrowsmith , Laurie Ailles , Brian Raught , Benjamin H. Lok

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引用次数: 0

Abstract

Small cell lung cancer (SCLC) is a highly aggressive form of cancer, commonly treated with DNA-damaging therapies such as chemotherapy and radiotherapy. Unfortunately, relapse occurs early and frequently, suggesting that epigenetic mechanisms may play a role in this aggressive behavior. Targeting these mechanisms during initial treatment could potentially enhance anti-cancer effects. This study investigated the combination of DNA-damaging treatments with a panel of Epigenetic Chemical Probes (EpiProbes). Among these, MS023, a PRMT inhibitor, showed the greatest synergy with cisplatin and etoposide across various SCLC cell lines. The cytotoxicity of MS023 was correlated with PRMT1 gene expression and protein levels. BioID analysis revealed that many PRMT1 interactors are involved in mRNA splicing. Mechanistic validation demonstrated that MS023 impaired RNA splicing, increased DNA:RNA hybrids, and caused DNA double-strand breaks (DSBs). When combined with ionizing radiation (IR), MS023 significantly increased DSBs, as indicated by γH2AX foci. Additionally, MS023 enhanced the effects of IR and the PARP inhibitor talazoparib, both in vitro and in vivo. Therefore, targeting PRMT1 in combination with DNA-damaging therapies presents a promising strategy to improve treatment outcomes for SCLC.

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PRMT1抑制剂MS023抑制RNA剪接使小细胞肺癌对DNA损伤剂敏感

小细胞肺癌（SCLC）是一种高度侵袭性的癌症，通常采用化疗和放疗等dna损伤疗法进行治疗。不幸的是，复发发生得早且频繁，这表明表观遗传机制可能在这种攻击行为中起作用。在初始治疗中靶向这些机制可能潜在地增强抗癌效果。本研究探讨了dna损伤治疗与一组表观遗传化学探针（EpiProbes）的结合。其中，PRMT抑制剂MS023与顺铂和依托泊苷在各种SCLC细胞系中表现出最大的协同作用。MS023的细胞毒性与PRMT1基因表达和蛋白水平相关。BioID分析显示许多PRMT1相互作用物参与mRNA剪接。机制验证表明，MS023损伤RNA剪接，增加DNA:RNA杂交，并导致DNA双链断裂（DSBs）。当与电离辐射（IR）联合时，MS023显著增加dsb，如γ - h2ax焦点所示。此外，MS023在体外和体内均增强了IR和PARP抑制剂talazoparib的作用。因此，靶向PRMT1联合dna损伤治疗是改善SCLC治疗结果的一种有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neoplasia 医学-肿瘤学

CiteScore

9.20

自引率

2.10%

发文量

审稿时长

26 days

期刊介绍： Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.