Abstract
Krüppel-associated box zinc finger proteins (KRAB-ZFPs) constitute the largest family of transcriptional factors exerting co-repressor functions in mammalian cells. In general, KRAB-ZFPs have a dual structure. They may bind to specific DNA sequences via zinc finger motifs and recruit a repressive complex through the KRAB domain. Such a complex mediates histone deacetylation, trimethylation of histone 3 at lysine 9 (H3K9me3), and subsequent heterochromatization. Nevertheless, apart from their repressive role, KRAB-ZFPs may also co-activate gene transcription, likely through interaction with other factors implicated in transcriptional control. KRAB-ZFPs play essential roles in various biological processes, including development, imprinting, retroelement silencing, and carcinogenesis. Cancer cells possess multiple genomic, epigenomic, and transcriptomic aberrations. A growing number of data indicates that the expression of many KRAB-ZFPs is altered in several tumor types, in which they may act as oncogenes or tumor suppressors. Hereby, we review the available literature describing the oncogenic and suppressive roles of various KRAB-ZFPs in cancer. We focused on their association with the clinicopathological features and treatment response, as well as their influence on the cancer cell phenotype. Moreover, we summarized the identified upstream and downstream molecular mechanisms that may govern the functioning of KRAB-ZFPs in a cancer setting.
Highlights
Introduction to Epigenetic Mechanisms Regulating GeneTranscription in CancerCancer development comprises a variety of genetic and epigenetic events
Additional studies indicated that cytosine arabinoside chemotherapeutic used in leukemias augmented the expression of ZNF224, which was accompanied by enhanced apoptosis [147]
The increasing amount of data demonstrates that KRAB-ZFP factors play an essential role in cancer biology, both as oncogenes or tumor suppressors
Summary
Cancer development comprises a variety of genetic and epigenetic events. Hanahan and Weinberg proposed a solid foundation for understanding tumor biology based on the characteristic cancer hallmarks [1,2]. Genetic causes of oncogenesis are well studied and are considered the main force of tumor transformation They lead to the loss, amplification, changed sequence or structure of a number of genes, altering the amount or functioning of the proteins that may drive carcinogenic processes. Tumor suppressor genes (TSGs), which are involved in cell proliferation, apoptosis, DNA repair, or immune response, are frequently silenced by the hypermethylation within gene promoter [4,21]. Other epigenetic events, such as post-translational histone modification (PTMs), chromatin 3D organization, and nucleosome positioning, are dysregulated in cancer cells. This review will discuss known examples of KRAB-ZFPs acting as oncogenes or TSGs, summarize their influence on cancer biology, and present molecular mechanisms responsible for their function
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