Emily S Reardon1, Vivek Shukla1, Sichuan Xi1, Sudheer K Gara1, Yi Liu1, David Straughan1, Mary Zhang1, Julie A Hong1, Eden C Payabyab1, Anju Kumari1, William G Richards2, Assunta De Rienzo2, Raffit Hassan3, Markku Miettinen4, Liqiang Xi4, Mark Raffeld4, Lisa T Uechi5, Xinmin Li5, Ruihong Wang1, Haobin Chen1, Chuong D Hoang1, Raphael Bueno2, David S Schrump6. 1. Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 2. Division of Thoracic Surgery, Brigham and Women's Hospital, Boston, Massachusetts. 3. Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 4. Laboratory of Pathology; National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 5. Microarray Core Facility, University of California, Los Angeles School of Medicine, Los Angeles, California. 6. Thoracic Epigenetics Section, Thoracic Surgery Branch, Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: david_schrump@nih.gov.
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.
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.
Authors: Anne S Tsao; O Wolf Lindwasser; Alex A Adjei; Prasad S Adusumilli; Matthew L Beyers; Gideon M Blumenthal; Raphael Bueno; Bryan M Burt; Michele Carbone; Suzanne E Dahlberg; Marc de Perrot; Dean A Fennell; Joseph Friedberg; Ritu R Gill; Daniel R Gomez; David H Harpole; Raffit Hassan; Mary Hesdorffer; Fred R Hirsch; Julija Hmeljak; Hedy L Kindler; Edward L Korn; Geoffrey Liu; Aaron S Mansfield; Anna K Nowak; Harvey I Pass; Tobias Peikert; Andreas Rimner; Bruce W S Robinson; Kenneth E Rosenzweig; Valerie W Rusch; Ravi Salgia; Boris Sepesi; Charles B Simone; Rajeshwari Sridhara; Peter Szlosarek; Emanuela Taioli; Ming-Sound Tsao; Haining Yang; Marjorie G Zauderer; Shakun M Malik Journal: J Thorac Oncol Date: 2018-09-25 Impact factor: 15.609
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