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UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma
- Source :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 16(1)
- Publication Year :
- 2020
-
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.
- 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
Subjects
Details
- ISSN :
- 15561380
- Volume :
- 16
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Accession number :
- edsair.doi.dedup.....350285e5c10685bf9fd5b227873d2470