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UHRF1 is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma
Journal of Thoracic Oncology ( IF 20.4 ) Pub Date : 2021-01-01 , DOI: 10.1016/j.jtho.2020.08.024
Emily S Reardon 1 , Vivek Shukla 1 , Sichuan Xi 1 , Sudheer K Gara 1 , Yi Liu 1 , David Straughan 1 , Mary Zhang 1 , Julie A Hong 1 , Eden C Payabyab 1 , Anju Kumari 1 , William G Richards 2 , Assunta De Rienzo 2 , Raffit Hassan 3 , Markku Miettinen 4 , Liqiang Xi 4 , Mark Raffeld 4 , Lisa T Uechi 5 , Xinmin Li 5 , Ruihong Wang 1 , Haobin Chen 1 , Chuong D Hoang 1 , Raphael Bueno 2 , David S Schrump 1
Affiliation  

OBJECTIVE Ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) encodes a master regulator of DNA methylation that has emerged as an epigenetic driver in human cancers. To date, no studies have examined UHRF1 in malignant pleural mesothelioma (MPM). The present study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. METHODS Micro-array, qRT-PCR, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMC) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. Impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-seq, proliferation, invasion and colony formation assays, as well as murine xenograft experiments were performed to examine gene expression and growth of MPM cells following biochemical or pharmacologic inhibition of UHRF1 expression. RESULTS UHRF1 expression was significantly higher in MPM lines/specimens relative to NMC/ normal pleura. Asbestos induced UHRF1 expression in NMC. Over-expression of UHRF1 was associated with decreased overall survival in MPM patients. UHRF1 knockdown reversed genome-wide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, as well as growth of MPM xenografts. These effects were phenocopied by the repurposed chemotherapeutic agent, mithramycin. Biochemical or pharmacologic up-regulation of p53 significantly reduced UHRF1 expression in MPM cells. RNA-seq experiments demonstrated pleiotropic effects of UHRF1 down-regulation, and identified novel, clinically relevant biomarkers of UHRF1 expression in MPM. CONCLUSIONS UHRF1 is an epigenetic driver in MPM. These findings support efforts to target UHRF1 expression/activity for mesothelioma therapy.

中文翻译:

UHRF1 是恶性胸膜间皮瘤的新型可药用表观遗传靶点

具有植物同源结构域和无名指结构域 1 (UHRF1) 的泛素样编码 DNA 甲基化的主要调节因子,该调节因子已成为人类癌症的表观遗传驱动因素。迄今为止,还没有研究检查 UHRF1 在恶性胸膜间皮瘤 (MPM) 中的作用。本研究旨在探索靶向 UHRF1 在 MPM 中的治疗潜力。方法 微阵列、qRT-PCR、免疫印迹和免疫组织化学技术用于评估在有或没有石棉、MPM 系、正常胸膜和原发性 MPM 标本培养的正常间皮细胞 (NMC) 中 UHRF1 的表达。使用两个独立的数据库评估 UHRF1 表达对 MPM 患者生存的影响。RNA-seq、增殖、侵袭和集落形成测定,以及鼠异种移植实验,以检查 UHRF1 表达的生化或药理学抑制后 MPM 细胞的基因表达和生长。结果 相对于 NMC/正常胸膜,MPM 系/标本中的 UHRF1 表达显着更高。石棉在 NMC 中诱导 UHRF1 表达。UHRF1 的过表达与 MPM 患者的总生存期降低有关。UHRF1 敲低逆转了全基因组 DNA 低甲基化,抑制了 MPM 细胞的增殖、侵袭和克隆形成,以及 MPM 异种移植物的生长。这些作用被重新利用的化学治疗剂光神霉素进行了表型复制。p53 的生化或药理学上调显着降低了 MPM 细胞中 UHRF1 的表达。RNA-seq 实验证明了 UHRF1 下调的多效性,并确定了 MPM 中 UHRF1 表达的新的、临床相关的生物标志物。结论 UHRF1 是 MPM 的表观遗传驱动因素。这些发现支持针对间皮瘤治疗的 UHRF1 表达/活性的努力。
更新日期:2021-01-01
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