In mammals, DNA methyltransferases DNMT1 and DNMT3’s (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer.

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Epigenetic regulation in conjunction with signaling pathways, play crucial roles in pluripotency, cell differentiation, and transcriptional plasticity in cancer. Indeed, a third of all cancers aberrantly express pluripotency genes and retain stemness, allowing for cancer recurrence following chemo- or radiotherapy. Vascular Endothelial Zinc Finger 1 (VEZF1) is a transcription factor expressed ubiquitously in adult tissues. VEZF1 null ESCs retain alkaline phosphatase staining postdifferentiation, suggesting a potential role of VEZF1 in pluripotency exit. However, the role of VEZF1 in pluripotency maintenance and exit is novel. Using mouse embryonic stem cells as a model system for pluripotency maintenance and exit, we sought to determine the regulatory role of VEZF1 in pluripotency. Our data indicate that ESCs derived from Vezf1 knockout mice (Vezf1 KO) show higher expression of pluripotency genes than Wildtype (WT) cells. Increased expression of pluripotency genes was confirmed upon the temporal ablation of Vezf1 in ESCs using a Doxycycline-inducible knockdown system. Interestingly, we observed that Vezf1 KO ESCs show severe defects in the repression of the pluripotency program postdifferentiation. Our analysis of VEZF1 ChIP-Seq data in ESCs revealed the binding of VEZF1 to promoters of multiple genes involved in canonical WNT and MAPK signaling. The WNT and MAPK signaling pathways are crucial for pluripotency maintenance and exit. Therefore, we proposed that VEZF1 enhances the inducible expression of WNT signaling genes in normal and cancer cells. To test this hypothesis, we performed RNA-Seq analysis which showed decreased expression of WNT signaling genes in Vezf1 KO ESCs, supporting the role of VEZF1 in Wnt signaling. Previous data indicate a significant overlap of VEZF1 and CTCF genome-wide. Therefore, to gain insights into the mechanism of gene regulation by VEZF1, we performed CTCF ChIP-Seq in WT and Vezf1 null cells. Our data revealed an increase in CTCF binding in the absence of VEZF1 compared to WT cells. The unique CTCF binding profile in Vezf1 KO cells was associated with genes involved in WNT and MAPK signaling pathways, both of which regulate pluripotency. This observation suggests that Vezf1 occludes CTCF from repressing WNT signaling genes. Our study of VEZF1 in ESCs suggests that the reduced expression of Vezf1 in cancer cells will potentially support the formation of cancer stem cells. Indeed, we have observed reduced expression of Vezf1 in F9 embryonal carcinoma cells (ECCs). Notably, F9 ECCs exhibit incomplete repression of pluripotency genes akin to Vezf1 KO ESCs. Collectively, this novel study emphasizes the importance of VEZF1 in regulating pluripotency and will expand our understanding of the development of stemness in cancer cells toward developing effective therapeutics against cancer. Citation Format: Isaiah K. Mensah, Martin Emerson, Hern Tan, Ming He, Humaira Gowher. Vascular endothelial zinc finger 1 promotes stemness by regulating key signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 329.

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