CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions
Johannes JungSonja BuismanEllen WeersingAlbertina Dethmers-AusemaErik ZwartHein SchepersMike R. DekkerSeka LazareFranziska HammerlYulia SkokovaSusanne M. KooistraKarin KlaukeRaymond A. PootLeonid BystrykhGerald de Haan
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Abstract:
In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia.Keywords:
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Polycomb group (PcG) proteins are overexpressed in several human malignancies including breast cancer. In particular, aberrant expression of BMI1 and EZH2 has been linked to metastasis and poor prognosis in cancer patients. At present, very little is known about the pharmacological inhibitors of PcG proteins. Here we show that histone deacetylase inhibitors (HDACi) downregulate expression of BMI1. Treatment of MCF10A cells, which are immortal non-transformed breast epithelial cells, and breast cancer cells with HDACi led to decreased expression of BMI1. We further show that downregulation of BMI1 by HDACi results due to the transcriptional downregulation of BMI1 gene. Specifically, we show that primary transcription and promoter activity of BMI1 is suppressed upon treatment with HDACi. Furthermore, downregulation of BMI1 was accompanied by a decrease in histone 2A lysine 119 ubiquitination (H2AK119Ub), which is catalyzed by BMI1 containing polycomb repressive complex 1. HDACi treatment also led to derepression of growth inhibitory genes and putative tumor suppressors, which are known to be silenced by PcG proteins and polycomb repressive complexes (PRCs). In summary, our findings suggest that BMI1 is an important therapy target of HDACi, and that HDACi can be used alone or in combination with other therapies to inhibit growth of tumors that overexpress PcG proteins such as BMI1.
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Background: Colorectal cancer (CRC) is one of the most common cancers worldwide. CRC therapy is still a serious problem because of the presence of cancer stem cells (CSCs) within the tumor. BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) is one of the important molecules for self-renewal of the CSCs and a component of poly comb repressive complex 1 that plays an important role in stimulating the progression of the cell cycle through epigenetic inhibition of tumor suppressors. BMI1 is a marker of colon stem cells that its expression increases in colorectal CSCs. The inhibition of BMI1 expression by miRNA could be one of the promising treatment options in CRC. Furthermore, investigating the regulation of BMI1 expression by miRNAs during tumorigenesis could be valuable in the identification of molecular mechanisms involved in CRC. Our aim was to conduct a bioinformatics analysis of known tumor suppressor miRNAs in CRC that have a potential to inhibit BMI1 expression. Methods: The presence of BMI-1, as a potential target of the selected miRNAs, was explored in various databases of miRNA target prediction including TargetScan, DIANA-microT, PicTar, miRanada, miRtar, mirMAP, and miRDB. These databases are based on algorithms such as miRNA-target interactions and thermodynamic stability (ΔG). miRNA with the highest score was selected according to the prediction score. Results: According to bioinformatics analysis, the highest score was derived for miR-330-3p. As a new miRNA to suppress BMI-1, miR-330-3p can be used in applied studies. Conclusions: Compared to other tumor suppressor miRNAs in CRC, miR-330-3p has the greatest probability to inhibit BMI1. Therefore, the experimental validation of miR-330-3p/BMI1 axis would be useful in identifying novel therapeutics and biomarkers in CRC.
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It was shown that after treatment by Ca2+- and Mg2+-dependent DNAses and subsequent dosed ultrasonication the fractions of active and relatively inactive chromatins isolated from liver cell nuclei of rats differing in age contain all main types of histones, but differ considerably in the relative amounts of individual fractions of these proteins. In all age groups studied the proteins of relatively inactive chromatin are largely histones, while the amount of non-histone proteins is higher in active chromatin. In the course of postnatal development the amount of histones in both chromatin fractions is increased and that of non-histone proteins is decreased. This is probably due to heterochromatization of the chromatin complex in liver cells with ageing. In the course of postnatal ontogenesis the spectrum of non-histone proteins in both chromatin fractions is changed.
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The polycomb group protein BMI1 is an important regulator of cancer stem cell (CSC) phenotype and is often overexpressed in cancer cells. Its overexpression leads to increase in CSC fraction and therapy resistance in tumors. BMI1 functions via polycomb repressive complex 1 (PRC1)-mediated gene silencing and also via PRC1-independent transcriptional activities. At present, very little is known about the therapy reagents that can efficiently inhibit BMI1 expression, and the CSC phenotype. Here, we report that the polo-like kinase 1 (PLK1) regulates BMI1 expression, and that its inhibition can efficiently down-regulate BMI1 expression and PRC1 activity, and induce premature senescence in breast cancer cells. We also show that the exogenous BMI1 overexpression mitigates anti-oncogenic effects of PLK1 inhibition and overcomes senescence induction by PLK1 inhibitors. We further show that PLK1 inhibition down-regulates BMI1 by upregulating the miRNA-200c/141 cluster, which encodes miR-200c and miR-141, both of which are known to post-transcriptionally downregulate BMI1 expression. Thus, our data suggest that PLK1 inhibitors can be successfully used to inhibit growth of tumors in which PcG protein BMI1 is overexpressed or the PRC1 activity is deregulated.
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Polycomb group protein BMI1 is an important regulator of senescence, aging, and cancer. On one hand, it is overexpressed in cancer cells and is required for self-renewal of stem cells. On the other hand, it is downregulated during senescence and aging. MicroRNAs have emerged as major regulators of almost every gene associated with cancer, aging, and related pathologies. At present, very little is known about the miRNAs that regulate the expression of BMI1. Here, we report that miR-141 posttranscriptionally downregulates BMI1 expression in human diploid fibroblasts (HDFs) via a miR-141 targeting sequence in the 3' untranslated region of BMI1 mRNA. We also show that overexpression of miR-141 induces premature senescence in HDFs via targeting of BMI1 in normal but not in exogenous BMI1-overexpressing HDFs. Induction of premature senescence in HDFs was accompanied by upregulation of p16INK4a, an important downstream target of BMI1 and a major regulator of senescence. Our results suggest that miR-141-based therapies could be developed to treat pathologies where BMI1 is deregulated.
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Polycomb group (PcG) protein BMI1 is an important regulator of oncogenic phenotype and is often overexpressed in several human malignancies including breast cancer. Aberrant expression of BMI1 is associated with metastasis and poor prognosis in cancer patients. At present, therapy reagents that can efficiently inhibit the expression of BMI1 are not very well known. Here, we report that Timosaponin A‐III (TA‐III), a steroidal saponin obtained from the rhizomes of an herb, Anemarrhena asphodeloides , strongly inhibits expression of BMI1 in breast cancer cells. Treatment of breast cancer cells with TA‐III resulted in inhibition of oncogenic phenotypes such as proliferation, migration and invasion, and induction of cellular senescence. Inhibition of these oncogenic phenotypes was accompanied by downregulation of BMI1 expression and histone posttranslational modification activity of PRC1. The mechanistic analysis of TA‐III‐induced inhibition of oncogenic activity and BMI1 expression suggests that downregulation of c‐Myc mediates TA‐III effect on BMI1. We further show that exogenous BMI1 overexpression can overcome TA‐III‐induced inhibition of oncogenic phenotypes. We also show that TA‐III induces expression of tumor suppressive miR‐200c and miR‐141, which are negatively regulated by BMI1. In summary, our data suggest that TA‐III is a potent inhibitor of BMI1 and that it can be successfully used to inhibit the growth of tumors where PcG protein BMI1 and PcG activities are upregulated.
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Histone-modifying enzymes
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