Regulation of expression of the protein called ubiquitin-like with plant homeodomain and ring finger domains 1 (UHRF1) may impact survival in patients with malignant pleural mesothelioma, according to findings published in the Journal of Thoracic Oncology.
UHRF1 is a protein encoded by the UHRF1 gene. It is a component of multiprotein complex that is involved in recruiting DNMT1, a DNA methyltransferase, that catalyzes the transfer of methyl groups to specific CpG structures in DNA. UHRF1 is overexpressed in several human malignancies, and may drive tumorigenesis by silencing tumor promoter genes through hypermethylation, as well as activating endogenous retroviral sequences through hypomethylation.
The aim of this study was to investigate the potential role of UHRF1 as an epigenetic driver in malignant pleural mesothelioma.
Based on the results of cell studies, xenograft experiments in mice, as well as the interrogation of large databases of genomic alterations and patient-specific information across cancers, the following findings were reported:
- Expression of UHRF1 was significantly higher in malignant pleural mesothelioma cells compared with normal human mesothelial cells.
- Ten-day exposure of normal human mesothelial cells to crocidolite asbestos showed a dose-dependent upregulation of UHRF1.
- The proliferation of malignant pleural mesothelioma cells, and the growth of malignant pleural mesothelioma xenografts, were inhibited by the knockdown of UHRF1.
- Based on patient outcome and RNA sequencing data from The Cancer Genome Atlas (TCGA), an inverse relationship between UHRF1 expression and overall survival in patients with malignant pleural mesothelioma was observed.
Regarding these findings, the study authors noted, “whereas further studies are necessary to confirm these observations and to ascertain the molecular basis for this phenomenon, our data support prospective studies to determine if UHRF1 over-expression is a biomarker of poor treatment response and decreased survival in MPM patients.”
Although no specific inhibitors of UHRF1 currently exist or are being investigated in clinical trials, results of cell studies investigating the following available agents on the regulation of UHRF1 showed the following:
- Intraperitoneal treatment with mithramycin, an activator of p53, diminished UHRF1 expression in subcutaneous mesothelioma xenografts in athymic nude mice.
- Investigational inhibitors of HDM2-mediated ubiquitination of p53 downregulated UHRF1 and DNMT1 in malignant pleural mesothelioma cells.
Regarding these latter findings, the study authors commented that “collectively, the results strongly suggest that augmentation of p53 signaling either by repurposed drugs such as mithramycin or HDM2 inhibitors under clinical development may be an effective strategy to target UHRF1 expression in MPM.”
In summarizing the results of this study, the study authors noted that their findings “suggest that UHRF1 is a novel druggable epigenetic target for patients with mesotheliomas regardless of the heterogeneity of these tumors. Future studies pertaining to the role of UHRF1 in the pathogenesis and prognosis of pleural mesotheliomas are warranted.”
- Reardon ES, Shukla V, Xi S, et al. UHRF1 is a novel druggable epigenetic target in malignant pleural mesothelioma. J Thorac Oncol. Published online September 11, 2020. doi:10.1016/j.jtho.2020.08.024