锌指蛋白X连锁1（ZNFX1）是癌症中表观遗传诱导的病原体模拟和炎性小体信号传导中的一种新型主调控因子。
ZNFX1 is a Novel Master Regulator in Epigenetically-induced Pathogen Mimicry and Inflammasome Signaling in Cancer.
作者信息
Stojanovic Lora, Abbotts Rachel, Tripathi Kaushlendra, Coon Collin M, Rajendran Saranya, Farid Elnaz Abbasi, Hostetter Galen, Guarnieri Joseph W, Wallace Douglas C, Liu Sheng, Wan Jun, Calendo Gennaro, Marker Rebecca, Gohari Zahra, Inayatullah Mohammed M A, Tiwari Vijay K, Kader Tanjina, Santagata Sandro, Drapkin Ronny, Kommoss Stefan, Pfisterer Jacobus, Konecny Gottfried E, Coopergard Ryan, Issa Jean-Pierre, Winterhoff Boris J N, Topper Michael J, Sandusky George E, Miller Kathy D, Baylin Stephen B, Nephew Kenneth P, Rassool Feyruz V
机构信息
University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA.
Division of Translational Radiation Sciences, Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
出版信息
bioRxiv. 2024 Oct 21:2024.10.18.618659. doi: 10.1101/2024.10.18.618659.
DNA methyltransferase and poly(ADP-ribose) polymerase inhibitors (DNMTis, PARPis) induce a stimulator of interferon (IFN) genes (STING)-dependent pathogen mimicry response (PMR) in ovarian (OC) and other cancers. We now show that combining DNMTis and PARPis upregulates expression of a little-studied nucleic-acid sensor, NFX1-type zinc finger-containing 1 protein (ZNFX1). We demonstrate that ZNFX1 is a novel master regulator for PMR induction in mitochondria, serving as a gateway for STING-dependent PMR. In patient OC databases, high ZNFX1 expression levels correlate with advanced stage disease. ZNFX1 expression alone significantly correlates with an increase in overall survival in a phase 3 trial for therapy-resistant OC patients receiving bevacizumab in combination with chemotherapy. In correlative RNA-seq data, inflammasome signaling through ZNFX1 correlates with abnormal vasculogenesis. ZNFX1 controls PMR signaling through the mitochondria and may serve as a biomarker to facilitate offering personalized therapy in OC patients, highlighting the strong translational significance of our findings.
DNA甲基转移酶和聚（ADP - 核糖）聚合酶抑制剂（DNMTis，PARPis）在卵巢癌（OC）和其他癌症中诱导干扰素（IFN）基因刺激物（STING）依赖性病原体模拟反应（PMR）。我们现在表明，联合使用DNMTis和PARPis可上调一种研究较少的核酸传感器——含NFX1型锌指蛋白1（ZNFX1）的表达。我们证明ZNFX1是线粒体中PMR诱导的新型主要调节因子，作为STING依赖性PMR的门户。在患者OC数据库中，高ZNFX1表达水平与晚期疾病相关。在一项针对接受贝伐单抗联合化疗的治疗抵抗性OC患者的3期试验中，单独的ZNFX1表达与总生存期的增加显著相关。在相关的RNA测序数据中，通过ZNFX1的炎性小体信号传导与异常血管生成相关。ZNFX1通过线粒体控制PMR信号传导，可能作为一种生物标志物，有助于为OC患者提供个性化治疗，突出了我们研究结果的强大转化意义。
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