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Gene expression profiling of BIX01294-treated human neuroblastoma cell line BE(2)-C

ABSTRACT: Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51512 | GEO | 2013/10/23

SECONDARY ACCESSION(S): PRJNA223386

REPOSITORIES: GEO

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Gene expression profiling of BIX01294-treated human neuroblastoma cell line BE(2)-C

Project description:Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer. Affymetrix microarray assays were performed according to the manufacturer's directions on total RNA isolated from three independent samples of BE(2)-C cells treated either with 0.05% DMSO or with 5 M-BM-5M BIX01294 (B9311, Sigma-Aldrich) for 24 hours.

2013-10-23 | E-GEOD-51512 | biostudies-arrayexpress

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing

Project description:PALI1 is a newly identified accessory protein of the Polycomb Repressive Complex 2 (PRC2) that catalyzes H3K27 methylation. However, the roles of PALI1 in cancer are yet to be defined. Here we report that PALI1 is upregulated in advanced prostate cancer (PCa) and competes with JARID2 for binding to PRC2 core subunit SUZ12. PALI1 further interacts with the H3K9 methyltransferase G9A, bridging the formation of a unique G9A-PALI1-PRC2 super-complex that occupies a subset of G9A-target genes to mediate dual H3K9/K27 methylation and gene repression. Many of these genes are developmental regulators induced upon cell differentiation, and their loss in PCa predicts poor prognosis. Accordingly, PALI1 and G9A drive PCa cell proliferation and invasion in vitro and xenograft tumor growth in vivo. Collectively, our study shows that PALI1 harnesses two central epigenetic mechanisms to suppress cellular differentiation and promote tumorigenesis, which can be targeted by dual EZH2 and G9A inhibition.

2022-12-12 | GSE175697 | GEO

PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing [RNA-seq]

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PALI1 Promotes Tumor Growth through Competitive Recruitment of PRC2 to G9A-target Chromatin for Dual Epigenetic Silencing [RNA-Seq II]

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Small molecule activation of PKM in cancer cells induces serine auxotrophy

Project description:Proliferating tumor cells use aerobic glycolysis to support their high metabolic demands. Paradoxically, increased glycolysis is often accompanied by expression of the lower activity PKM isoform, effectively constraining lower glycolysis. Here, we report the discovery of novel PKM activators with a unique allosteric binding mode. Characterization of how these compounds impact cancer cells revealed an unanticipated link between glucose and amino acid metabolism. PKM activation resulted in a metabolic rewiring of cancer cells manifested by a profound dependency on the non-essential amino acid serine for continued cell proliferation. Induction of serine auxotrophy by PKM activation was accompanied by reduced carbon flow into the serine biosynthetic pathway and increased expression of high affinity serine transporters. These data support the hypothesis that PKM expression confers metabolic flexibility to cancer cells that allows adaptation to nutrient stress. A549 cancer cells were treated with compound-16 for up to 24 hours in the presence and absence of serine in the media.

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Investigation of the role of histone modification propagating activity of GLP

Project description:We use ChIP-Seq and RNA-Seq technology to profile the H3K9me2 modification and transcription under different conditions of GLP activity. GLP and G9a are major H3K9 dimethylases, and are essential for mouse early embryonic development. Here we report that GLP and G9a possess intrinsic histone methylation propagating activities. The histone methyltransferase activities of GLP and G9a are stimulated by neighboring nucleosomes pre-methylated at H3K9. These stimulation events function in cis and are dependent on H3K9 methylation binding activities of ankyrin repeats domains in GLP and G9a. In mouse embryonic stem cells (ESCs) harboring a mutant GLP lacking H3K9 methylation propagating activity, pluripotent genes display a delayed kinetics in establishing H3K9 methylation and gene silencing during differentiation. Disruption of the H3K9 methylation propagating activity of GLP in mice causes growth retardation of the embryos, ossification defects of calvaria and early postnatal lethality. We propose that GLP¡¯s ability to rapidly propagate H3K9 methylation is required for efficient gene silencing during programmed cell fate transition. H3K9me2 and H3K9me1 are ChIPped and sequenced in WT mESC and GLP-mutant mESCs, and RNA-Seq was done for those cells as well.

2015-01-20 | E-GEOD-54412 | biostudies-arrayexpress

Dynamics of de novo heterochromatin assembly and disassembly at replication forks ensures fork stability

Project description:Chromatin is dynamically reorganized when DNA replication forks are challenged. However, the process of epigenetic reorganization and its implication for fork stability is poorly understood. Here, we discover a checkpoint regulated cascade of chromatin signaling that activates 5 the histone methyltransferase EHMT2/G9a to catalyze heterochromatin assembly at stressed replication forks. Using biochemical and single molecule chromatin fiber approaches, we show that G9a together with SUV39h1 induces chromatin compaction by accumulating the repressive modifications, H3K9me1/me2/me3, in the vicinity of stressed replication forks. This closed conformation is also favored by the G9a-dependent exclusion of the H3K9-demethylase 10 JMJD1A/KDM3A, which facilitates heterochromatin disassembly upon fork restart. Untimely heterochromatin disassembly from stressed forks by KDM3A enables PRIMPOL access, triggering ssDNA gap formation and sensitizing cells towards chemotherapeutic drugs. These findings may help explaining chemotherapy resistance and poor prognosis observed in cancer patients displaying elevated level of G9a/H3K9me3.

2023-05-12 | PXD041742 | Pride

Investigation of the role of histone modification propagating activity of GLP

2015-01-20 | GSE54412 | GEO

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.

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