Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

Alhosin, Mahmoud; Omran, Ziad; Zamzami, Mazin A.; Al-Malki, Abdulrahman L.; Choudhry, Hani; Mousli, Marc; Bronner, Christian

doi:10.1186/s13046-016-0453-5

Cited by 86 publications

(82 citation statements)

References 109 publications

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“…H3K9 methylation and DNA methylation are well known to contribute to gene repression [37]. While this mechanism has never been described in a parasite infection model, in sporadic breast cancer, UHRF1 was shown to induce DNA methylation, as well as histone deacetylation and methylation on the BRCA1 promoter by recruitment of an inhibitory transcriptional complex similar to the one we observed here [42]. The SRA domain of UHRF1 directly interacts with 5-hydroxymethylcytosine and hemi-methylated DNA and PCNA, which helps to recruit DNMT1 and stimulate its enzymatic activity [22,43].…”

Section: Discussionsupporting

confidence: 75%

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Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways

Sabou

Doderer-Lang

Leyer

et al. 2019

Cell. Mol. Life Sci.

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Toxoplasmosis, caused by the apicomplexan parasite Toxoplasma gondii, is one of the most common infections in the world due to the lifelong persistence of this parasite in a latent stage. This parasite hijacks host signaling pathways through epigenetic mechanisms which converge on key nuclear proteins. Here, we report a new parasite persistence strategy involving T. gondii rhoptry protein ROP16 secreted early during invasion, which targets the transcription factor UHRF1 (ubiquitinlike containing PHD and RING fingers domain 1), and leads to host cell cycle arrest. This is mediated by DNMT activity and chromatin remodeling at the cyclin B1 gene promoter through recruitment of phosphorylated UHRF1 associated with a repressive multienzymatic protein complex. This leads to deacetylation and methylation of histone H3 surrounding the cyclin B1 promoter to epigenetically silence its transcriptional activity. Moreover, T. gondii infection causes DNA hypermethylation in its host cell, by upregulation of DNMTs. ROP16 is already known to activate and phosphorylate protective immunity transcription factors such as STAT 3/6/5 and modulate host signaling pathways in a strain-dependent manner. Like in the case of STAT6, the strain-dependent effects of ROP16 on UHRF1 are dependent on a single amino-acid polymorphism in ROP16. This study demonstrates that Toxoplasma hijacks a new epigenetic initiator, UHRF1, through an early event initiated by the ROP16 parasite kinase.Keywords Toxoplasma gondii · UHFR1 · ROP16 · Cyclin B1 · DNMT · Epigenetic regulation Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionsupporting

confidence: 75%

“…In bacteria-or virusinduced host gene reprogramming, targets are the MAPK, IFN and NF-κB signaling pathways [49]. Well known in cancer development [24,42], but unknown in host-pathogen interactions, we show the role played by UHRF1 during Toxoplasma parasitic infection.…”

Section: Discussionmentioning

confidence: 80%

Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways

Sabou

Doderer-Lang

Leyer

et al. 2019

Cell. Mol. Life Sci.

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“…Cancer cells undergo global DNA hypomethylation, whereas some regions, on the contrary, undergo hypermethylation, e.g. promoters of tumor suppressor genes [ 7 , 8 ]. On the histone code versant, several modifications have been reported in various types of cancer [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer

et al. 2017

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Cancer is one of the deadliest diseases in the world causing record number of mortalities in both developed and undeveloped countries. Despite a lot of advances and breakthroughs in the field of oncology still, it is very hard to diagnose and treat the cancers at early stages. Here in this review we analyze the potential of Ubiquitin-like containing PHD and Ring Finger domain 1 (UHRF1) as a universal biomarker for cancers. UHRF1 is an important epigenetic regulator maintaining DNA methylation and histone code in the cell. It is highly expressed in a variety of cancers and is a well-known oncogene that can disrupt the epigenetic code and override the senescence machinery. Many studies have validated UHRF1 as a powerful diagnostic and prognostic tool to differentially diagnose cancer, predict the therapeutic response and assess the risk of tumor progression and recurrence. Highly sensitive, non-invasive and cost effective approaches are therefore needed to assess the level of UHRF1 in patients, which can be deployed in diagnostic laboratories to detect cancer and monitor disease progression.

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“…In keeping with the previous studies, we found a signi cant negative correlation between the expression of UHRF1 and p53 in AML patients. UHRF1 is frequently activated in various malignancies and plays various oncogenic roles particularly by repression of TSGs [41].…”

Section: Discussionmentioning

confidence: 99%

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

Amiri

Mohammadi

Rafiee

et al. 2020

Preprint

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Introduction Epigenetic alterations could cause leukemia through the activation of normally silent loci or silencing of normally active loci. We herein aimed to compare the expression patterns of a histone modifiers panel consisted of SUV39H1, PRDM16, UHRF2, KDM2B, and KDM3C between acute myeloid leukemia(AML) cells and normal cells and to assess the correlation of these genes with the expression of vital tumor suppressor genes, including p16INK4A and p53.Materials and methods Bone marrow or peripheral blood samples of 50 AML patients at diagnosis and also 18 subjects with a normal hematopoietic system as a control group were obtained after informed consent. Then, qRT-PCR was performed to determine the expression levels of the aforementioned genes. Results We found a broad alteration in the expression signature of five out of seven studied genes in AML patients as compared with the control group. UHRF2 and p53 were remarkably downregulated in AML patients (P < 0.001), while SUV39H1, PRDM16, and KDM3C significantly overexpressed (P< 0.01). Based on the Spearman rank correlation, SUV39H1, KDM2B, and age of the patients negatively regulated both p16INK4A and p53 expression. Conclusion Taken together, our findings provided preliminary evidence regarding the pervasive mRNA perturbation of histone modifiers and their plausible influences on critical tumor suppressor genes. Future studies in this area would be required to assist in establishing these results in the clinical practice of AML patients.

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Signalling pathways in UHRF1-dependent regulation of tumor suppressor genes in cancer

Cited by 86 publications

References 109 publications

Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways

Toxoplasma gondii ROP16 kinase silences the cyclin B1 gene promoter by hijacking host cell UHRF1-dependent epigenetic pathways

The epigenetic integrator UHRF1: on the road to become a universal biomarker for cancer

Transcription Analysis of a Histones Modifiers Panel Coupled with Tumor Suppressor Genes Displayed Frequent Changes in Acute Myeloid Leukemia-Related Genes

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