Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy
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Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy Dorota Komar* and Przemyslaw Juszczynski
Abstract Background: With the discovery that more than half of human cancers harbor mutations in chromatin proteins, deregulation of epigenetic mechanisms has been recognized a hallmark of malignant transformation. Posttranslational modifications (PTMs) of histone proteins, as main components of epigenetic regulatory machinery, are also broadly accepted as therapeutic target. Current “epigenetic” therapies target predominantly writers, erasers and readers of histone acetylation and (to a lesser extent) methylation, leaving other types of PTMs largely unexplored. One of them is the phosphorylation of serine 10 on histone H3 (H3S10ph). Main body: H3S10ph is emerging as an important player in the initiation and propagation of cancer, as it facilitates cellular malignant transformation and participates in fundamental cellular functions. In normal cells this histone mark dictates the hierarchy of additional histone modifications involved in the formation of protein binding scaffolds, transcriptional regulation, blocking repressive epigenetic information and shielding gene regions from heterochromatin spreading. During cell division, this mark is essential for chromosome condensation and segregation. It is also involved in the function of specific DNA–RNA hybrids, called R-loops, which modulate transcription and facilitate chromosomal instability. Increase in H3S10ph is observed in numerous cancer types and its abundance has been associated with inferior prognosis. Many H3S10-kinases, including MSK1/2, PIM1, CDK8 and AURORA kinases, have been long considered targets in cancer therapy. However, since these proteins also participate in other critical processes, including signal transduction, apoptotic signaling, metabolic fitness and transcription, their chromatin functions are often neglected. Conclusions: H3S10ph and enzymes responsible for deposition of this histone modification are important for chromatin activity and oncogenesis. Epigenetic-drugs targeting this axis of modifications, potentially in combination with conventional or targeted therapy, provide a promising angle in search for knowledge-driven therapeutic strategies in oncology. Keywords: Histone modifications, Kinases, H3, H3S10ph, Phosphorylation, Chromatin modifications, Cancer, Cancer therapy
*Correspondence: [email protected] Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Gandhi 14 Str, 02‑776 Warsaw, Poland
Background Recent large-scale cancer genome projects like The Cancer Genome Atlas highlighted the role of epigenetic alterations in cancer development, as they revealed that about half of human cancers harbors mutations in chromatin-modifying proteins [1]. Post-translational modifications (PTMs) of histone proteins are main
© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0 International Licens
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