UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma

Our plain-English summary of UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma, by E.S. Reardon, V. Shukla, S. Xi, et al (Journal of Thoracic Oncology, 2021).

The study

• Authors: E.S. Reardon, V. Shukla, S. Xi, S.K. Gara, Y. Liu, D. Straughan, M. Zhang, J.A. Hong, E.C. Payabyab, A. Kumari, W.G. Richards, A. De Rienzo, R. Hassan, M. Miettinen, L. Xi, M. Raffeld, L.T. Uechi, X. Li, R. Wang, H. Chen, C.D. Hoang, R. Bueno, D.S. Schrump
• Journal: Journal of Thoracic Oncology
• Published: 2021;16(1):89-103
• Cited by: 33 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

In plain English

This laboratory study looked at a protein called UHRF1 in malignant pleural mesothelioma. UHRF1 helps control DNA methylation, a set of chemical tags that switch genes on and off. The authors measured UHRF1 in mesothelioma cell lines, normal mesothelial cells and patient tumor samples. UHRF1 levels were significantly higher in mesothelioma cells than in normal mesothelial cells. It was found in all 49 mesothelioma specimens tested, and it was not detected in 11 normal mesothelial samples. When normal mesothelial cells were grown in the lab with crocidolite asbestos for 10 days, UHRF1 rose as the dose increased. Among 155 patients in a Brigham and Women's Hospital database, median survival was 8.7 months for those with high UHRF1 and 22.2 months for those with low UHRF1. Lowering UHRF1 slowed the growth of mesothelioma cells in the lab and in mice. The drug mithramycin also lowered UHRF1. The authors concluded that UHRF1 is a novel druggable target in mesothelioma. They noted that patients in the two survival databases may have differed in characteristics and treatment, and that sarcomatoid tumors could not be evaluated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study using cell lines, patient tumor specimens, survival analysis of two patient databases, and mouse xenograft experiments
• Who was studied: Normal mesothelial cells (LP3, LP9), mesothelioma cell lines (H2052, H2452, H28, MES1-3, MES7-10), a normal pleura culture (NP1), 49 mesothelioma specimens (26 treatment-naive patients plus a tissue microarray) and 11 normal mesothelial samples. Survival data came from 87 patients in The Cancer Genome Atlas (TCGA) and 155 patients at Brigham and Women's Hospital (131 epithelioid, 24 non-epithelioid).
• Exposure: LP9 normal mesothelial cells were grown with or without crocidolite asbestos (1-2 micrograms per square centimeter, printed as ug/cm2) for 10 days. Mesothelioma cells were also tested with UHRF1 knock-down and with the drugs mithramycin, RITA and RG7388.
• Main results:
  • UHRF1 mRNA and protein levels were significantly higher in mesothelioma cell lines than in normal mesothelial cells
  • UHRF1 was found in all 49 mesothelioma specimens, and 18 (37%) showed intermediate or high staining. It was not detected in 11 unpaired normal mesothelial samples.
  • In LP9 normal mesothelial cells, 10-day crocidolite exposure raised UHRF1 in a dose-dependent way
  • In TCGA patients, UHRF1 expression levels correlated inversely with overall survival
  • In the Brigham and Women's Hospital cohort of 155 patients, median overall survival was 8.7 months with high UHRF1 versus 22.2 months with low UHRF1 (HR 3.61; 95% CI 2.48-5.28; p less than 0.001)
  • In multivariate analysis of the Brigham and Women's Hospital cohort, high UHRF1 expression remained associated with poor survival (HR 3.29; 95% CI 2.19-4.93; p less than 0.001)
  • Among patients with epithelioid mesothelioma, median overall survival was 14.0 months for females with UHRF1-high tumors and 40.7 months for females with UHRF1-low tumors (HR 4.7; 95% CI 2.5-8.3; p less than 0.001). Males had 15.5 months with UHRF1-low tumors and 7.5 months with UHRF1-high tumors.
  • Knocking down UHRF1 significantly inhibited proliferation of mesothelioma cells in the lab
  • Knocking down UHRF1 significantly decreased invasion of MES1 cells in the lab and growth of MES1 tumors in athymic nude mice
  • Mithramycin down-regulated UHRF1 in cultured mesothelioma cells
  • Mithramycin given into the abdomen (IP) markedly reduced UHRF1 in MES1 tumors grown under the skin of mice
  • The drugs RITA and RG7388 lowered UHRF1 in a dose-dependent way in MES1 and MES7 cells. Only RITA lowered UHRF1 in H2452 cells, which carry mutant p53.
  • RNA-sequencing analysis identified 12 potential biomarkers of UHRF1 expression and poor prognosis
• The authors' conclusion: The authors concluded that UHRF1 is a novel druggable epigenetic target in mesothelioma. They suggested that the rise in UHRF1 seen after asbestos exposure in normal mesothelial cells may be an early event in malignant transformation.
• Limitations the authors state:
  • Patients in the two databases used for survival analysis may have differed in demographics and treatment
  • The effect of UHRF1 in sarcomatoid mesothelioma could not be evaluated because of cell line and database limitations
  • No obvious association was seen between UHRF1 and disease stage, possibly because of database limitations
  • The findings on gender and survival need confirmation in further studies

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, Mesothelial Cells, Pleura, Overall Survival, Biomarker, Mesothelioma.

Related studies

• HDAC1-mSin3a-NCOR1, Dnmt3b-HDAC1-Egr1 and Dnmt1-PCNA-UHRF1-G9a regulate the NY-ESO1 gene expression — P.F. Cartron, C. Blanquart, et al. (2013)
• Gli as a novel therapeutic target in malignant pleural mesothelioma — H. Li, N. Lui, et al. (2013)
• Exposing Hidden Targets: Combining epigenetic and immunotherapy to overcome cancer resistance — K. Olino, T. Park, et al. (2020)
• Anetumab ravtansine: a novel mesothelin-targeting antibody-drug conjugate cures tumors with heterogeneous target expression favored by bystander effect — S. Golfier, C. Kopitz, et al. (2014)
• HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma — S. Tsuji, K. Washimi, et al. (2017)
• Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma — V. Laszlo, M.A. Hoda, et al. (2015)

Browse more research in Journal of Thoracic Oncology, or return to medical research.