UHRF1 Is a Novel Druggable Epigenetic Target in Malignant Pleural Mesothelioma

Epigenetic Modifier UHRF1 May Be a Potential Target in Malignant Pleural Mesothelioma

“…18 Mithramycin is a clinically approved DNA-binding antitumor antibiotic and has previously been reported to interact with core histones 19 and impact DNA methylation patterns. 20 Numerous recognition elements for SP1 (activator) and p53 (repressor) have been identified within the UHRF1 promoter, and Reardon et al, 14 in this additional study, have illustrated that treatment with mithramycin reduced DNMT1 levels in MPM cells. In a subcutaneous MES1 xenograft in athymic nude mice, treatment with mithramycin reduced UHRF1 expression; however, the effect on DNMT1 was less remarkable, indicating that other pathways may be in play.…”

“…Initially identified as altered through Affymetrix microarray data, higher levels of UHRF1 mRNA and protein were confirmed in a broad panel of MPM cell lines (n ¼ 9) compared with normal mesothelial cells (n ¼ 2) by Reardon et al 14 . Microarray analysis also revealed increased expression of DNMTs and components of the PRC2.…”

“…Increased levels of UHRF1 are evident in several tumor types, leading to global DNA methylation and histone modifications, primarily in tumor suppressor genes and oncogenes, thus contributing to carcinogenesis. 13 However, little is known regarding this marker in MPM, which this recent study by Reardon et al 14 has sought to address.…”

“…Previous studies have found that targeting the epigenetic machinery is fraught with difficulty, and unfortunately, the preclinical promise is often not translated to clinical success; however, newer studies such as tazemetostat (EZH2 inhibitor) in BAP-mutated MPM are exhibiting promise. 21 This work by Reardon et al, 14 has identified a number of UHRF1-responsive targets and exhibited value in pursuing indirect and direct targeting of UHRF1 in MPM. Dual targeting with other epigenetic therapies and mithramycin may provide a potential vulnerability to exploit in the future, with further studies on this critical epigenetic modifier warranted.…”

Identification of Overexpressed Genes in Malignant Pleural Mesothelioma

“…In addition, their increased expression also was found in several human MPM cell lines [ 11 , 12 ]. Interestingly, an increased expression of MDK, UHRF1, and SPARC was observed in MPM tissues as well, and it correlated with poor patients’ OS together with elevated expression in MPM cell lines [ 13 , 14 , 15 ]. Thus, all these observations are in agreement with our results and strongly suggest that at least CTHRC1, E-selectin, SPARC, UHRF1, PRSS23, BAG2, MDK, KIF23, and MAD2L1 could play an important role in MPM carcinogenesis as biomarkers of prognosis, and constitute novel therapeutic targets for MPMs.…”