UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma

Emily S. Reardon, Vivek Shukla, Sichuan Xi, Sudheer K. Gara, Yi Liu, David Straughan, Mary Zhang, Julie A. Hong, Eden C. Payabyab, Anju Kumari, William G. Richards, Assunta De Rienzo, Raffit Hassan, Markku Miettinen, Liqiang Xi, Mark Raffeld, Lisa T. Uechi, Xinmin Li, Ruihong Wang, Haobin ChenChuong D. Hoang, Raphael Bueno, David S. Schrump

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish
Pages (from-to)89-103
Number of pages15
JournalJournal of Thoracic Oncology
Volume16
Issue number1
DOIs
StatePublished - Jan 2021

Keywords

  • DNMT1
  • Epigenetics
  • Malignant pleural mesothelioma
  • Prognosis
  • Therapeutic target
  • UHRF1

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