Mitogen-induced distinct epialleles are phosphorylated at either H3S10 or H3S28, depending on H3K27 acetylation

Khan, Dilshad H.; Healy, Shannon; He, Shihua; Lichtensztejn, Daniel; Klewes, Ludger; Sharma, Kiran; Lau, Veronica; Mai, Sabine; Delcuve, Geneviève P.; Davie, James R.

doi:10.1091/mbc.e16-08-0618

Cited by 12 publications

(15 citation statements)

References 43 publications

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“…Interphase phospho-H3S10 mark is deposited on actively transcribed genes by multiple kinases ( [64,97], formaldehyde [98], cigarette smoke [99], ionizing radiation [53], H3S10ph may represent a mechanistic link between carcinogens and cellular transformation. This hypothesis is supported by the studies indicating that TPA or epidermal growth factor (EGF)-induced MSK1 activity and H3S10ph is required for transformation of mouse epidermal cells [16,100].…”

Section: Interphase Kinasesmentioning

confidence: 99%

“…Multiple IEGs encode transcription factors, such as c-MYC, c-FOS, c-JUN, FOS1L, EGR1 , that are responsible for transcriptional reprogramming of cells exposed to environmental stress-inducing stimuli. Since many of these IEGs are oncogenes, and H3S10 phosphorylation is typically triggered by factors known to be potentially carcinogenic, such as exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) [ 64 , 97 ], formaldehyde [ 98 ], cigarette smoke [ 99 ], ionizing radiation [ 53 ], H3S10ph may represent a mechanistic link between carcinogens and cellular transformation. This hypothesis is supported by the studies indicating that TPA or epidermal growth factor (EGF)-induced MSK1 activity and H3S10ph is required for transformation of mouse epidermal cells [ 16 , 100 ].…”

Section: Interphase Kinasesmentioning

confidence: 99%

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Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Komar

Juszczyński

2020

Clin Epigenet

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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.

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Section: Interphase Kinasesmentioning

confidence: 99%

Section: Interphase Kinasesmentioning

confidence: 99%

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Komar

Juszczyński

2020

Clin Epigenet

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“… 38 H3K27 acetylation and S28 phosphorylation are directly coupled, and such combination can functionally antagonize PRC2-mediated H3K27me3 mark. 39 Using a NIR inducible knockdown cell line, we found that silencing of NIR resulted in increased H3K27ac and reduction of H3K27me3 level at the promoter region of FOXO3, implying the intricated balance of H3K27ac and H3K27me3 levels by NIR through modulating PRC2 activity. Since NIR has INHAT (inhibitor of histone acetyltransferase) activity, the interaction of NIR and EZH2 may block the accessibility of acetyltransferases to catalyze H3K27ac, while facilitating PRC2 to catalyze the H3K27me3 mark.…”

Section: Discussionmentioning

confidence: 88%

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Chen¹,

Dong²,

Wang³

et al. 2021

OTT

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Background: Novel inhibitor of histone acetyltransferase repressor (NIR), a corepressor with a novel inhibitor of histone acetyltransferase (INHAT) activity, has been reported to be a negative modulator of p53 and a regulator of the cell cycle in cancer cells. However, the role of NIR in the progression of breast cancer remains elusive. Materials and Methods: Oncomine database was used to analyze the mRNA levels and prognosis value of NIR in breast cancer. We performed loss-of-function and gain-of-function studies using lentivirus expressing shRNA targeting NIR, enhancer of zeste homolog 2 (EZH2) and forkhead box O3 (FOXO3) or lentivirus expressing NIR or FOXO3, respectively. Cell proliferation and colony formation assays were performed. Coimmunoprecipitation (Co-IP) and immunoprecipitation (IP) were performed to identify the interaction between NIR and polycomb repressive complex 2 (PRC2) subunits. ChIP assay was used to identify the enrichment of NIR, EZH2, H3K27ac and H3K27me3 at the FOXO3 promoter region and the regulation of H3K27 modification at the FOXO3 promoter by NIR. Results: High levels of NIR expression were correlated with poor prognosis in breast cancer patients. Knockdown of NIR suppressed the proliferation of breast cancer cells. Mechanically, NIR was recruited by EZH2 to the promoter vicinity of FOXO3 via direct protein-protein interaction. Silencing NIR increased H3K27ac and decreased H3K27me3 levels at the FOXO3 promoter, resulting in enhancing FOXO3 expression. In accordance with this, growth inhibition of breast cancer cells caused by silencing of NIR could be reversed by FOXO3 knockdown. Conclusion: NIR knockdown inhibited proliferation by switching the H3K27me3 and H3K27ac marks at the FOXO3 promoter to promote FOXO3 transcription, and this effect depends on the physical interaction between NIR and PRC2 in breast cancer cells. Our results suggest that NIR might be a potential target for breast cancer treatment.

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“…In contrast, a study investigating such a histone modification in OSCC showed its relationship with tumorigenesis and poor outcomes . Also, H3S10ph may be directly involved in tumorigenesis by inducing the transcription of some developmental genes, including Hox and immediate‐early genes . In another study, the MYC proto‐oncogene protein product was shown to be able to activate cancer‐promoting genes by recruiting the H3S10ph kinase PIM‐1 .…”

Section: Discussionmentioning

confidence: 94%

Prognostic value of histone H3 serine 10 phosphorylation and histone H4 lysine 12 acetylation in oral squamous cell carcinoma

et al. 2018

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Mitogen-induced distinct epialleles are phosphorylated at either H3S10 or H3S28, depending on H3K27 acetylation

Cited by 12 publications

References 43 publications

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Rebelled epigenome: histone H3S10 phosphorylation and H3S10 kinases in cancer biology and therapy

Knockdown of NIR Suppresses Breast Cancer Cell Proliferation via Promoting FOXO3

Prognostic value of histone H3 serine 10 phosphorylation and histone H4 lysine 12 acetylation in oral squamous cell carcinoma

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