PARP1-DOT1L transcription axis drives acquired resistance to PARP inhibitor in ovarian cancer

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Cancer Pub Date : 2024-05-22 DOI:10.1186/s12943-024-02025-8

Chaohua Liu, Jiana Li, Fei Xu, Lihua Chen, Mengdong Ni, Jiangchun Wu, Haiyun Zhao, Yangjun Wu, Jiajia Li, Xiaohua Wu, Xiaojun Chen

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Abstract

Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance poses a significant challenge in ovarian carcinoma (OC). While the role of DOT1L in cancer and chemoresistance is acknowledged, its specific role in PARPi resistance remains unclear. This study aims to elucidate the molecular mechanism of DOT1L in PARPi resistance in OC patients. This study analyzed the expression of DOT1L in PARPi-resistant cell lines compared to sensitive ones and correlated it with clinical outcomes in OC patients. Comprehensive in vitro and in vivo functional experiments were conducted using cellular and mouse models. Molecular investigations, including RNA sequencing, chromatin immunoprecipitation (ChIP) and Cleavage Under Targets and Tagmentation (CUT&Tag) assays, were employed to unravel the molecular mechanisms of DOT1L-mediated PARPi resistance. Our investigation revealed a robust correlation between DOT1L expression and clinical PARPi resistance in non-BRCA mutated OC cells. Upregulated DOT1L expression in PARPi-resistant tissues was associated with diminished survival in OC patients. Mechanistically, we identified that PARP1 directly binds to the DOT1L gene promoter, promoting transcription independently of its enzyme activity. PARP1 trapping induced by PARPi treatment amplified this binding, enhancing DOT1L transcription and contributing to drug resistance. Sequencing analysis revealed that DOT1L plays a crucial role in the transcriptional regulation of PLCG2 and ABCB1 via H3K79me2. This established the PARP1-DOT1L-PLCG2/ABCB1 axis as a key contributor to PARPi resistance. Furthermore, we discovered that combining a DOT1L inhibitor with PARPi demonstrated a synergistic effect in both cell line-derived xenograft mouse models (CDXs) and patient-derived organoids (PDOs). Our results demonstrate that DOT1L is an independent prognostic marker for OC patients. The PARP1-DOT1L/H3K79me2-PLCG2/ABCB1 axis is identified as a pivotal contributor to PARPi resistance. Targeted inhibition of DOT1L emerges as a promising therapeutic strategy for enhancing PARPi treatment outcomes in OC patients.

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PARP1-DOT1L 转录轴驱动卵巢癌患者对 PARP 抑制剂产生获得性耐药性

多聚（ADP-核糖）聚合酶抑制剂（PARPi）耐药性是卵巢癌（OC）的一大挑战。虽然 DOT1L 在癌症和化疗耐药性中的作用已得到公认，但它在 PARPi 耐药性中的具体作用仍不清楚。本研究旨在阐明DOT1L在OC患者PARPi耐药中的分子机制。本研究分析了与敏感细胞株相比，DOT1L在PARPi耐药细胞株中的表达情况，并将其与OC患者的临床预后相关联。研究利用细胞和小鼠模型进行了全面的体外和体内功能实验。为了揭示DOT1L介导的PARPi耐药的分子机制，我们采用了包括RNA测序、染色质免疫沉淀（ChIP）和靶标下裂解及标记（CUT&Tag）检测在内的分子研究方法。我们的研究发现，在非BRCA突变的OC细胞中，DOT1L的表达与临床PARPi耐药之间存在密切的相关性。PARPi耐药组织中DOT1L表达上调与OC患者存活率降低有关。从机理上讲，我们发现 PARP1 可直接与 DOT1L 基因启动子结合，从而促进转录，而与其酶活性无关。PARPi治疗诱导的PARP1捕获扩大了这种结合，增强了DOT1L的转录并导致耐药性。测序分析表明，DOT1L 通过 H3K79me2 在 PLCG2 和 ABCB1 的转录调控中起着关键作用。这就确定了 PARP1-DOT1L-PLCG2/ABCB1 轴是 PARPi 耐药性的关键因素。此外，我们发现在细胞系衍生的异种移植小鼠模型（CDXs）和患者衍生的器官组织（PDOs）中，将 DOT1L 抑制剂与 PARPi 结合使用可产生协同效应。我们的研究结果表明，DOT1L是OC患者的独立预后标志物。PARP1-DOT1L/H3K79me2-PLCG2/ABCB1轴被认为是PARPi耐药的关键因素。靶向抑制 DOT1L 是一种很有前景的治疗策略，可提高 PARPi 对 OC 患者的治疗效果。

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

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

期刊介绍： Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.