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Methylation-dependent and -independent roles of EZH2 coordinately contribute to CDCA8 activation in prostate cancer

ABSTRACT: Cell division cycle associated 8 (CDCA8) is a component of chromosomal passenger complex (CPC) that participates in mitotic regulation. Although cancer-related CDCA8 hyperactivation has been widely observed, its molecular mechanism remains elusive. Here, we report that CDCA8 overexpression maintains tumorigenicity and is associated with poor clinical outcome in patients with prostate cancer (PCa). Notably, enhancer of zeste homologue 2 (EZH2) is identified to be responsible for CDCA8 activation in PCa. Genome-wide assays revealed that EZH2-induced H3K27 trimethylation represses let-7b expression and thus protects the let-7b-targeting CDCA8 transcripts. More importantly, EZH2 facilitates the self-activation of E2F1 by recruiting E2F1 to its own promoter region in a methylation-independent manner. The high level of E2F1 further promotes transcription of CDCA8 along with the other CPC subunits. Taken together, our study suggests that EZH2-mediated cell cycle regulation in PCa relies on both its methyltransferase and non-methyltransferase activities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184740 | GEO | 2021/09/30

REPOSITORIES: GEO

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EZH2 enables germinal center formation through epigenetic silencing of CDKN1A and an Rb-E2F1 positive feedback loop

Project description:The EZH2 histone methyltransferase is required for B cells to form germinal centers (GCs). Here we show that EZH2 mediates GC formation through repression of cyclin-dependent kinase inhibitor CDKN1A (p21Cip1). Deletion of Cdkn1a rescued the GC reaction in Ezh2 knockout mice. To study the effects of EZH2 in primary GC B cells we generated and validated a 3D B cell follicular organoid system that mimics the endogenous GC reaction. Using this system we found that depletion of EZH2 suppressed G1 to S phase transition of GC B cells in a Cdkn1a dependent manner. GC B cells of Cdkn1a;Ezh2 double knockout mice exhibited high levels of phospho Rb, indicating that loss of Cdkn1a allows progression of cell cycle. Moreover, we show that the transcription factor E2F1 plays a major role in inducing EZH2 upregulation during the GC reaction. E2F1 deficient mice manifest impaired GC responses, which was rescued by restoring EZH2 expression, thus defining a positive feedback loop whereby EZH2 controls GC B cell proliferation by suppressing CDKN1A, allowing cell cycle progression with a concomitant phosphorylation of Rb and release of E2F1.

2017-08-10 | GSE95491 | GEO

Identifying transcriptional targets of ONECUT3 by RNAseq

Project description:We report the direct target genes of the aberrant expression of ONECUT3 through next generation sequencing. We combine RNA-seq and ChIP-seq to identify target genes of ONECUT3 overexpression. RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) assays were performed on TP53-KO mouse embryonic fibroblast MEF with or without Doxycycline (100 ng/ml) to identify target genes both bound and regulated by ONECUT3. We found that genes related with sister chromosome exchange separation, mitotic nuclear division, and chromosome segregation were significantly upregulated by high level of ONECUT3. The top 10 directly activated target genes predicted by Binding and Expression Target Analysis (BETA) include Incenp and Cdca8, which are the critical components of Chromosomal Passenger Complex (CPC). Through this observation, we conclude that main role of ONECUT3 as transcription factors is to upregulate mRNA transcription of mitotic process. This sutdy provide new insight of genetic network of how dysfunctional ONECUT3 underlies mitotic defects and Chromosomal instability.

2024-03-01 | GSE202693 | GEO

Identifying transcriptional targets of ONECUT3 by ChIP-seq

2024-03-01 | GSE202680 | GEO

E2F1 transcription factor knockdown effect on gene expression in LNCaP-abl cells

Project description:Our computational approach identified E2F1 as a potential collaborator of EZH2 in androgen-independent prostate cancer. This experiment is to designed to validate the crosstalking of E2F1 and EZH2 pathways. We showed that majority of the EZH2-induced genes in androgen-independent prostate tumor cells are in downstream of E2F1, providing insight into the EZH2-E2F1 collaborative regulatory pathway.

2016-01-22 | GSE56331 | GEO

Transcriptome analysis of NCC-IT-A3 cells by Barasertib treatment

Project description:During mitosis, the chromosomal passenger complex (CPC) that is formed by Aurora-B, INCENP, Survivin, and Borealin ensures the faithful segregation of the chromosomes into daughter cells. We previously have shown that CPC activity was terminated by the anaphase promoting complex/cyclosome (APC/C) and its cofactor Cdh1 via ubiquitylation of Borealin and Aurora-B during the G1 phase of somatic cells. On the other hand, protein levels of Borealin and Aurora-B were stable during cell cycle progression due to high levels of Emi1, which keep APC/CCdh1 inactive in embryonal carcinoma (EC) cells. During retinoic acid-induced differentiation of EC cells, these proteins were downregulated by APC/CCdh1-mediated ubiquitylation. Interestingly, CPC proteins form a complex with Aurora-B kinase activity even in interphase of EC cells. Significantly, inhibition of CPC activity by either knockdown of Borealin or Aurora-B and Aurora-B kinase inhibitor treatment induced spontaneous differentiation of EC cells. In conclusion, sustained CPC activity plays a critical role in maintenance of the undifferentiated state of pluripotent stem cells. We therefore propose an interphase role of the CPC in regulating embryonic pluripotency.

2021-07-09 | GSE179503 | GEO

Mass spectrometry analysis of chromosomal passenger complex proteins and kinetochore proteins in Trypanosoma brucei

Project description:We performed chemical crosslinking mass spectrometry of native protein complexes purified from Trypanosoma brucei procyclic cells to obtain protein-protein interaction information for the chromosomal passenger complex (CPC) and kinetochore complex. Crosslinks among CPC subunits were detected using YFP-AUK1, while those among KKT8 complex subunits were detected in the YFP-KKIP1 sample. We also performed immunoprecipitation and mass spectrometry of CPC subunits (full-length proteins and fragments) to identify co-purifying proteins.

2023-10-13 | PXD045987 | Pride

Utilizing HXMS to Uncover Structural Basis of CPC Phase Separation

Project description:The centromere is the locus that directs accurate chromosome segregation, and a mater regulatory complex ,the chromosome passenger comlex (CPC) is enriched in a region of the mitotic centromre termed the inner centromre. Recent findings support a role of CPC phase separation in its localization and function in mitotic error correction. Currently there are no teqhniques to globaly map the motifs on proteins that drive the multivalent interactions. In this context, we now employ hydrogen/deuterium exchange coupled to mass spectrometry (HXMS) to study dynamics of CPC phase separation.

2024-03-13 | PXD034374 | Pride

Methylation-dependent and -independent roles of EZH2 coordinately contribute to CDCA8 activation in prostate cancer

Project description:Methylation-dependent and -independent roles of EZH2 coordinately contribute to CDCA8 activation in prostate cancer

| PRJNA766037 | ENA

Next Generation Sequencing Facilitates Quantitative Analysis of HCC cells transfected with NCsiRNA or CDCA8siRNA

Project description:We hypothesized if targeting of CDCA8 with small interfering (si) RNA could inhibit HCC progression. We also investigated molecular mechanism to mediate HCC cell death caused by CDCA8 silencing. To accomplish this, Huh1 and Huh7 human HCC cells were transfected with CDCA8 siRNA and tested for growth inhibition and apoptotic induction using MTS, FACS and microscopic analysis. To obtain insights into the molecular changes in response to CDCA8 knockdown, global changes in gene expression were examined using RNA sequencing. As results, siRNA silencing of CDCA8 inhibited HCC cell growth by blocking cell-cycle progression and inducing apoptosis. RNA sequencing showed that, representatively, the anti-proliferative effects were driven by a subset of molecular alterations including the upregulation of tumor suppressive ATF3 and GADD34 genes, whereas a key regulator of cell growth and invasiveness BGLAP was repressed. Subsequent Western blotting also revealed that CDCA8 silencing decreases the levels of pro-caspase 3 and PARP-1, accelerating apoptotic signaling in HCC cells. In addition, targeting CDCA8 effectively suppressed HCC tumor growth growth in a murine xenograft model. Taken together, these findings suggest that CDCA8 could be a promising molecular target for systemic therapy of HCC.

2017-02-14 | GSE77992 | GEO

Gene expression changes initiated by miR-34c in Dicer/Pten double knockout mouse serous epithelial cancer

Project description:miR-34c inhibits Dicer/Pten double knockout mouse serous epithelial cancer cell proliferation by inducing cell cycle arrest and apoptosis. We found that miR-34c had a more dramatic effect on inhibiting tumor cell viability than let-7b. The action of miR-34c induced tumor cell cycle arrest in G1 phase and apoptosis and was accompanied with the regulation of key genes involved in cell proliferation and cell cycle G1/S transition. miR-34c suppressed the expression of EZH2 and MYBL2, which may transcriptionally and functionally activate CDKN1C. Total RNA was extracted from DKO tumor cell lines transfected with miR-34c (n=3) and control miRNA (n=3).

2014-10-03 | E-GEOD-57493 | biostudies-arrayexpress

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