Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy.
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. Post-translational 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.
['Komar|Dorota|D|0000-0003-3447-1532', 'Juszczynski|Przemyslaw|P|']
D001695:Biology D063646:Carcinogenesis D002843:Chromatin D002986:Clinical Trials as Topic D019175:DNA Methylation D044127:Epigenesis, Genetic D000081122:Epigenome D006657:Histones D006801:Humans D058990:Molecular Targeted Therapy D009369:Neoplasms D010766:Phosphorylation D010770:Phosphotransferases D011499:Protein Processing, Post-Translational D000080870:R-Loop Structures D012694:Serine
Phosphorylation Kinases Cancer H3 H3S10ph Histone modifications Cancer therapy Chromatin modifications