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The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis

ABSTRACT: The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis

PROVIDER: PRJNA595504 | ENA |

REPOSITORIES: ENA

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The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [RNA-seq]

Project description:Emerging evidence suggested that epigenetic regulators can exhibit both co-activator and co-repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in cellular contexts remains elusive. Here, we reported that KDM5C, a repressive histone demethylase, is unexpectedly required for estrogen/estrogen receptor alpha (ERa)-induced gene transcriptional activation to promote cell proliferation, while it suppresses the expression of type I interferons (IFNs) and interferon-stimulated genes (ISGs) to escape from immuno-surveillance. KDM5C-interacting protein, ZMYND8, is found to be accompanied with KDM5C in regulation of both subsets of genes. Mechanistically, during estrogen/ERa-induced gene transcriptional activation, ERa interacts and recruits KDM5C/ZMYND8 to active enhancers, where ERa masks KDM5C’s demethylase activity towards H3K4me2/3, converting KDM5C from a co-repressor to a co-activator. Furthermore, KDM5C and ZMYND8 are found to recruit the P-TEFb complex in a cooperative manner to activate estrogen/ERa-target genes. In contrast, KDM5C/ZMYND8 represses type I IFNs and ISGs through directly interfering TBK1 phosphorylation in an enzymatic-dependent manner. The combinatory effects of KDM5C’s dual activities in regulation of genes involved in both cell proliferation and immuno-escape lead to breast cancer cell proliferation in vitro and xenograft growth in mice. Taken together, we revealed a mechanism by which a repressive epigenetic regulator can be converted to a co-activator under specific signal cues to regulate specific gene programs, and the dual nature as both a co-repressor and co-activator together contributes to cancer development.

2021-03-17 | GSE141987 | GEO

The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [ChIP-seq]

2021-03-17 | GSE141986 | GEO

The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-03-17 | GSE141988 | GEO

The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [RNA-seq]

Project description:The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [RNA-seq]

| PRJNA595509 | ENA

The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [ChIP-seq]

Project description:The dual function of JmjC domain-containing protein KDM5C in both gene transcriptional activation and repression promotes breast cancer cell growth and tumorigenesis [ChIP-seq]

| PRJNA595510 | ENA

The Dual Function of KDM5C in Both Gene Transcriptional Activation and Repression Promotes Breast Cancer Cell Growth and Tumorigenesis.

Project description:Emerging evidence suggested that epigenetic regulators can exhibit both activator and repressor activities in gene transcriptional regulation and disease development, such as cancer. However, how these dual activities are regulated and coordinated in specific cellular contexts remains elusive. Here, it is reported that KDM5C, a repressive histone demethylase, unexpectedly activates estrogen receptor alpha (ERα)-target genes, and meanwhile suppresses type I interferons (IFNs) and IFN-stimulated genes (ISGs) to promote ERα-positive breast cancer cell growth and tumorigenesis. KDM5C-interacting protein, ZMYND8, is found to be involved in both processes. Mechanistically, KDM5C binds to active enhancers and recruits the P-TEFb complex to activate ERα-target genes, while inhibits TBK1 phosphorylation in the cytosol to repress type I IFNs and ISGs. Pharmacological inhibition of both ERα and KDM5C is effective in inhibiting cell growth and tumorigenesis. Taken together, it is revealed that the dual activator and repressor nature of an epigenetic regulator together contributes to cancer development.

| S-EPMC8097366 | biostudies-literature

Targeting transcriptional factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C

Project description:In this study, we screened KDM5C-binding proteins and found that Yin Yang 1 (YY1) interacts with KDM5C. Interestingly, a synergistic antitumor effect was exerted when both KDM5C and YY1 were depleted, and targeting YY1 appeared to be a vulnerability in KDM5C-deficient cancer cells. Mechanistically, KDM5C is essential for global YY1 chromatin recruitment, especially at promoters. Moreover, an intact KDM5C JmjC domain but not KDM5C histone demethylase activity is required for KDM5C-mediated YY1 chromatin binding.Transcriptional profiling revealed that dual inhibition of KDM5C and YY1 led to significantly increased transcriptional repression of many cell cycle- and apoptosis-related genes. In summary, our work demonstrates a synthetic lethal interaction between YY1 and KDM5C and suggests a therapeutic vulnerability that can be targeted using combination therapies.

2024-06-28 | GSE270719 | GEO

Targeting transcriptional factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C [CUT&Tag]

2024-09-02 | GSE275838 | GEO

Targeting transcriptional factor YY1 is synthetic lethal with loss of the histone demethylase KDM5C [RNA-Seq]

2024-06-28 | GSE270718 | GEO

The Histone Demethylase KDM5C Functions as a Tumor Suppressor in AML by Repression of B ivalently M arked Immature Genes

Project description:To uncover novel epigenetic regulators in AML, we performed an in vivo short hairpin RNA (shRNA) screen in the context of Cebpa mutant AML. This led to the identification of the Histone 3 Lysine 4 (H3K4) demethylase, KDM5C, as a novel tumor suppressor in AML. KDM5C potentially functions as a transcriptional repressor via its demethylase activity at promoters, and dysregulation could therefore have widespread consequences. Here, we found that reduced Kdm5c/KDM5C expression is associated with accelerated growth in both human and murine AML cell lines. In vivo, Kdm5c knockdown in a Cebpa mutant AML mouse model resulted in a more aggressive, immature and short-latency phenotype. Mechanistically, we show that knockdown of Kdm5c increased H3K4me3 globally. This translated into the up-regulation of a group of bivalently marked immature genes, resulting in a de-differentiation phenotype which could be reversed by modulating levels of pro-differentiation factors. Finally, we demonstrated that low levels of KDM5C were associated with a decrease in long-term disease-free survival, specifically in female patients. This emphasizes the clinical relevance of our findings and identifies KDM5C as a novel female-biased tumor suppressor in AML.

2023-03-10 | PXD016568 | Pride

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