The ZAR1 protein in cancer; from epigenetic silencing to functional characterisation and epigenetic therapy of tumour suppressors.

Abstract ZAR1, zygote arrest 1, is a zinc finger protein (C-terminus), which was initially identified in mouse oocytes. Later it was found that its expression is present in various human tissues e.g. lung and kidney. Interestingly, it was observed that in various tumour types the ZAR1 transcript is missing due to hypermethylation of its CpG island promoter, but not ZAR2. Since methylation of the ZAR1 promoter is described as a frequent event in tumourigenesis, ZAR1 could serve as a useful diagnostic marker in cancer screens. ZAR1 was described as a useful prognostic/diagnostic cancer marker for lung cancer, kidney cancer, melanoma and possibly liver carcinoma. Furthermore, ZAR1 was reactivated as a tumour suppressor by epigenetic therapy using CRISPR-dCas9 method. This method holds the potential to precisely target not only ZAR1 and reactivate tumour suppressors in a tailored cancer therapy. ZAR1 is highly conserved amongst vertebrates, especially its zinc finger, which is the relevant domain for its protein and RNA binding ability. ZAR1 is implicated in various cellular mechanisms including regulation of oocyte/embryo development, cell cycle control and mRNA binding, though little was known about the underlying mechanisms. ZAR1 was reported to regulate and activate translation through the binding to TCS translation control sequences in the 3’UTRs of its target mRNA the kinase WEE1. ZAR1 has a tumour suppressing function by inhibiting cell cycle progression. Here we review the current literature on ZAR1 focusing on structural, functional and epigenetic aspects. Characterising the cellular mechanisms that regulate the signalling pathways ZAR1 is involved in, could lead to a deeper understanding of tumour development and, furthermore, to new strategies in cancer treatment.