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G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia

ABSTRACT: G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia

PROVIDER: PRJNA512136 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8378630_1.fastq.gz	Fastqsanger.gz
	SRR8378630_2.fastq.gz	Fastqsanger.gz
	SRR8378631_1.fastq.gz	Fastqsanger.gz
	SRR8378631_2.fastq.gz	Fastqsanger.gz
	SRR8378632_1.fastq.gz	Fastqsanger.gz

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G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

Project description:Chronic hypoxia inhibits apoptosis to enhance survival of cancer cells. The mechanisms that prevent apoptosis under hypoxia are unclear. Here, we show that hypoxia induced G9a, a lysine methyltransferase, which methylates a tumor suppressor, Runt-related transcription factor 3 (RUNX3) at lysines 129 and 171. G9a-mediated methylation reduced transcriptional activity of RUNX3 by inhibiting interactions with its transcriptional cofactors, the core-binding factor-beta (CBF-beta) and p300, and also decreased the protein level of RUNX3 via Smurf1-mediated proteasomal degradation. Through ChIP-seq and gene expression profiling, G9a-mediated methylation inhibited expression of genes involved in apoptosis, thereby enhancing survival and proliferation of cancer cells both in vitro and vivo. Our results suggest G9a-dependent methylation of RUNX3 as a therapeutic target to control tumor growth.

2020-11-02 | GSE124481 | GEO

G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

Project description:G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia [ChIP-seq]

| PRJNA512137 | ENA

Negative regulation of RUNX3 activity by G9a-mediated protein methylation in hypoxia [array]

Project description:Chronic hypoxia inhibits apoptosis and cell cycle arrest in cancer cells, leading to cell survival, proliferation and angiogenesis. The mechanism for anti-apoptosis and cell proliferation in hypoxic cancer cells is still elusive. Here, we showed that hypoxia inactivates Runt-related transcription factor 3 (RUNX3), which is known to play as a tumor suppressor to induce apoptosis and cell cycle arrest in various cancers. RUNX3 is methylated under hypoxic conditions at lysines (K) 129 and 171 through its interaction with methyltranferase G9a. Gene expression profiling revealed that the mutations of K129 and 171 in RUNX3 induced the expression of genes related to apoptosis and cell cycle arrest under hypoxic conditions, indicating critical roles of the RNUX methylation in anti-apoptosis and cell proliferation. Moreover, K129 and 171 mutants, compared to G9a or G9a+RUNX3 control, showed significant reduction in apoptotic ability and tumor progression in xenograft models. Therefore, G9a-dependent methylation of RUNX3 is a novel target to inhibit cell proliferation and anti-apoptosis under hypoxic conditions during tumorigenesis.

2020-11-02 | GSE81693 | GEO

G9a-mediated methylation abrogates RUNX3 tumor suppressive activity to promote cancer cell survival under hypoxia

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

2020-11-02 | GSE124482 | GEO

G9a

Project description:Drosophila melanogaster G9a, G9a, is expressed in 3 baseline experiment(s);

| FBgn0040372 | ExpressionAtlas

G9a

Project description:Drosophila melanogaster G9a, G9a, is differentially expressed in 11 experiment(s);

| FBgn0040372 | ExpressionAtlas

Inhibition of the H3K9 methyltransferase epigenetic regulator G9A attenuates oncogenicity but provokes a survival response via activation of the hypoxia pathway

Project description:Epigenetic mechanisms play important roles in the regulation of tumorigenesis, and hypoxia-induced epigenetic changes may be key drivers of the adaptation of cancer cells to the hypoxic microenvironment typical of solid tumors. Previously, we showed that loss-of-function or inhibition of the oncogenic H3K9 methyltransferase G9A attenuates tumor growth and constitutes an important strategy for cancer management. However, the mechanisms by which blockade of G9A leads to a tumor suppressive effect remain poorly understood. Here, we show that G9A is highly expressed in breast cancer compared to normal breast tissue and is associated with poor prognosis in patients, where it may function as a potent oncogenic driver in this cancer type. In agreement with this, G9A inhibition leads to increased cell death, impaired cell migration, reduced cell cycle and downregulated anchorage-independent growth. Interestingly, whole transcriptome analysis revealed that a number of previously non-responsive genes become amenable to hypoxia following G9A inhibition, including many targets that drive cancer cell survival. This was accompanied by the upregulation of the hypoxia inducible factors HIF1A and HIF2A during the use of G9A inhibition to curb cancer cell growth even under normoxic conditions. Therefore, we show that G9A is a key mediator of oncogenic processes in breast cancer cells and cancer therapeutics involving G9A inhibition can be used successfully to attenuate oncogenicity. However, cancer cells mount a survival response via activation of the HIF pathway that may necessitate the additional suppression of HIF signaling for improved efficacy in the eradication of the disease.

2017-12-20 | GSE89891 | GEO

Hypoxia Abrogates Tumor-Suppressive Activities of C/EBPδ in Pancreatic Cancer.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a low 5-year survival rate of only 13%. Despite intense research efforts, PDAC remains insufficiently understood. In part, this is attributed to opposing effects of key players being unraveled, including the stroma but also molecules that act in a context-dependent manner. One such molecule is the transcription factor C/EBPδ, where we recently showed that C/EBPδ exerts tumor-suppressive effects in PDAC cells in vitro. To better understand the role of C/EBPδ in different contexts and the development of PDAC, we here build on these findings and assess the effect of C/EBPδ in a PDAC model in mice. We establish that the lack of oxygen in vivo-hypoxia-counteracts the tumor-suppressive effects of C/EBPδ, and identify a reciprocal feedback loop between C/EBPδ and HIF-1α. RNA sequencing of C/EBPδ-induced cells under hypoxia also suggests that the growth-limiting effects of C/EBPδ decrease with oxygen tension. Consequently, in vitro proliferation assays reveal that the tumor-suppressive activities of C/EBPδ are abrogated due to hypoxia. This study demonstrates the importance of considering major physiological parameters in preclinical approaches.

| S-EPMC11394991 | biostudies-literature

The identification of differentially downregulated genes in hypoxia or G9a overexpression.

Project description:To identify that differentially downregulated genes in hypoxia or G9a overexpression, we have employed whole genome microarray expression profiling. SNU484 cells expressing GFP or GFP-G9a vector under normoxic or hypoxic conditions was used to identify that differentially downregulated genes.

2015-01-07 | E-GEOD-64710 | biostudies-arrayexpress

The interactomes of RUNX1 and RUNX3 from Mus musculus T cells

Project description:Cellular binary fate decisions require the progeny to silence genes associated with the alternative fate. The major subsets of alpha:beta T cells have been extensively studied as a model system for fate decisions. While the transcription factor RUNX3 is required for the initiation of Cd4 silencing in CD8 T cell progenitors, it is not required to maintain the silencing of Cd4 and other helper T lineage genes. The other runt domain containing protein, RUNX1, silences Cd4 in an earlier T cell progenitor, but this silencing is reversed whereas the gene silencing after RUNX3 expression is not reverse. Therefore, we hypothesized that RUNX3 and not RUNX1 recruits other factors that maintains the silencing of helper T lineage genes in CD8 T cells. To this end, we performed a proteomics screen of RUNX1 and RUNX3 to determine candidate silencing factors.

2019-11-12 | PXD007511 | Pride

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