PO.BCS01.01 · 生物信息与计算

三阴性乳腺癌中EZH2与多巴胺D1受体信号之间的表观遗传-神经递质串扰

Epigenetic-neurotransmitter crosstalk between EZH2 and dopamine D1 receptor signaling in triple-negative breast cancer

编号 43 展板 5 时间 4/19 02:00–05:00 区域 Section 3 主讲 Maciej Pietrzak, PhD

分会场 Application of Bioinformatics to Cancer Biology 1

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作者与单位 Authors & Affiliations

Maciej Pietrzak¹, Xilal Y. Rima², Gautam Sarathy³, Shivani Dhekne³, Lara Rizotto⁴, Dario Palmieri⁴, Sanjay Gupta⁵, Daniel G. Stover⁶, Giovanni Nigita⁷, Eduardo Reátegui², Pierre Giglio⁸, Christian Rolfo⁷, Eswar Shankar³

¹Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH,²Department of Chemical and Biomolecular Engineering, The Ohio State University,, Columbus, OH,³Division of Medical Oncology, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH,⁴Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, The Ohio State University, Columbus, OH,⁵Department of Urology, School of Medicine, Case Western Reserve University, Cleveland, OH,⁶OSUCCC - James, Columbus, OH,⁷Division of Medical Oncology, Department of Internal Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH,⁸Department of Neurology, School of Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH

摘要 Abstract

中文摘要

三阴性乳腺癌（TNBC）仍然是一种临床上难以治疗的亚型，其定义为缺乏ER、PR和HER2，并以侵袭性进展和有限的治疗易感性为特征。EZH2是PRC2的催化亚基，通过沉积H3K27me3和抑制肿瘤抑制程序而成为TNBC中已知的致癌驱动因子。相比之下，多巴胺D1受体（DRD1）信号最近作为一种意料之外的肿瘤抑制轴而崭露头角。然而，EZH2介导的表观遗传抑制与DRD1介导的神经递质信号之间的机制性相互作用尚不清楚，这代表了理解癌症中神经-表观遗传整合的一个关键空白。我们假设EZH2和DRD1的协调性失调重编程了支配TNBC侵袭性的转录状态。我们在MDA-MB-231细胞中生成了CRISPR改造的EZH2和DRD1敲除（KO）细胞，并通过免疫印迹进行了验证。DRD1 KO显著增加了增殖和迁移，而EZH2 KO则减弱了生长并破坏了细胞骨架结构。值得注意的是，DRD1消除增强了EZH2活性，提示存在一个此前未被认识到的将多巴胺能信号与表观遗传抑制相联系的反馈环路。RNA-seq分析（每组n=4）揭示了转录网络的广泛重塑，具有离散的EZH2依赖性和DRD1依赖性特征（FDR < 0.05，|log2FC| > 2）。EZH2 KO选择性地诱导了细胞因子活性、钙离子结合、MHC II类相互作用，以及调控黏附、细胞间通讯、白细胞活化和轴突/突起导向的生物学过程，共同反映了细胞骨架重构和免疫调节性重编程。相比之下，DRD1 KO富集了信号受体结合、调节因子/激活因子活性、受体-配体相互作用，以及支配黏附、迁移和IL-10介导的炎症信号的通路，这与促侵袭、促炎症的表型一致。总之，这些数据勾勒出TNBC中一条协调的表观遗传-多巴胺能轴。DRD1缺失增强了EZH2驱动的炎症和迁移程序，而EZH2耗竭则激活了限制肿瘤侵袭性的黏附和免疫调节通路。靶向这一双重调控节点可能代表一种破坏促肿瘤转录环路并改善TNBC治疗结果的新策略（由DOD资助：W81XWH2010065，Eswar Shankar）。

查看英文原文 English abstract

Triple-negative breast cancer (TNBC) remains a clinically intractable subtype defined by the absence of ER, PR, and HER2 and characterized by aggressive progression and limited therapeutic vulnerabilities. EZH2, the catalytic subunit of PRC2, is a known oncogenic driver in TNBC through deposition of H3K27me3 and repression of tumor-suppressive programs. In contrast, dopamine D1 receptor (DRD1) signaling has recently emerged as an unexpected tumor-suppressive axis. However, the mechanistic interplay between EZH2-mediated epigenetic repression and DRD1-mediated neurotransmitter signaling is unknown, representing a critical gap in understanding neuro-epigenetic integration in cancer. We hypothesized that coordinated dysregulation of EZH2 and DRD1 reprograms are transcriptional states that govern TNBC aggressiveness. CRISPR-engineered EZH2 and DRD1 knockouts (KO) were generated in MDA-MB-231 cells and validated by immunoblotting. DRD1 KO significantly increased proliferation and migration, whereas EZH2 KO diminished growth and disrupted cytoskeletal architecture. Notably, DRD1 ablation enhanced EZH2 activity, indicating a previously unrecognized feedback loop linking dopaminergic signaling to epigenetic repression. RNA-seq profiling (n=4/group) revealed extensive remodeling of transcriptional networks with discrete EZH2- and DRD1-dependent signatures (FDR < 0.05, |log2FC| > 2). EZH2 KO selectively induced cytokine activity, calcium ion binding, MHC class II interactions, and biological processes regulating adhesion, cell-cell communication, leukocyte activation, and axon/projection guidance, collectively reflecting cytoskeletal restructuring and immune-modulatory reprogramming. In contrast, DRD1 KO enriched signaling receptor binding, regulator/activator activity, receptor-ligand interactions, and pathways governing adhesion, migration, and IL-10-mediated inflammatory signaling, consistent with a pro-invasive, pro-inflammatory phenotype. Together, these data delineate a coordinated epigenetic-dopaminergic axis in TNBC. DRD1 loss potentiates EZH2-driven inflammatory and migratory programs, while EZH2 depletion activates adhesion and immune-regulatory pathways that constrain tumor aggressiveness. Targeting this dual regulatory node may represent a novel strategy to disrupt pro-tumor transcriptional circuitry and improve therapeutic outcomes in TNBC (Supported by DOD: W81XWH2010065, Eswar Shankar).

利益披露 Disclosure

M. Pietrzak, None.. X. Y. Rima, None.. G. Sarathy, None.. S. Dhekne, None.. L. Rizotto, None.. D. Palmieri, None.. S. Gupta, None.. D. G. Stover, None.. G. Nigita, None.. E. Reátegui, None.. P. Giglio, None.. C. Rolfo, None.. E. Shankar, None.

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