1. UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma
- Author
-
Sudheer Kumar Gara, Lisa T. Uechi, Emily S. Reardon, Vivek Shukla, Chuong D. Hoang, William G. Richards, Anju Kumari, David S. Schrump, Raphael Bueno, Assunta De Rienzo, Raffit Hassan, Markku Miettinen, Sichuan Xi, Eden C. Payabyab, Mark Raffeld, Yi Liu, Haobin Chen, Julie A. Hong, David M. Straughan, Xin-Min Li, Mary Zhang, Rui-Hong Wang, and Liqiang Xi
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,Mesothelioma ,Lung Neoplasms ,Microarray ,Pleural Neoplasms ,Ubiquitin-Protein Ligases ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Gene expression ,medicine ,Animals ,Humans ,Epigenetics ,Cell Proliferation ,Gene knockdown ,business.industry ,Mesothelioma, Malignant ,medicine.disease ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,DNA methylation ,Cancer research ,CCAAT-Enhancer-Binding Proteins ,Immunohistochemistry ,business ,DNA hypomethylation - Abstract
Introduction 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 evaluated UHRF1 expression in malignant pleural mesothelioma (MPM). This study was undertaken to explore the therapeutic potential of targeting UHRF1 in MPM. Methods Microarray, real-time quantitative reverse transcription–polymerase chain reaction, immunoblot, and immunohistochemistry techniques were used to evaluate UHRF1 expression in normal mesothelial cells (NMCs) cultured with or without asbestos, MPM lines, normal pleura, and primary MPM specimens. The impact of UHRF1 expression on MPM patient survival was evaluated using two independent databases. RNA-sequencing, proliferation, invasion, and colony formation assays, and murine xenograft experiments were performed to evaluate gene expression and growth of MPM cells after biochemical or pharmacologic inhibition of UHRF1 expression. Results UHRF1 expression was significantly higher in MPM lines and specimens relative to NMC and normal pleura. Asbestos induced UHRF1 expression in NMC. The overexpression of UHRF1 was associated with decreased overall survival in patients with MPM. UHRF1 knockdown reversed genomewide DNA hypomethylation, and inhibited proliferation, invasion, and clonogenicity of MPM cells, and 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-sequencing experiments exhibited the 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 the efforts to target UHRF1 expression or activity for mesothelioma therapy.
- Published
- 2020