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CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [CHIP-seq]

ABSTRACT: CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [CHIP-seq]

PROVIDER: PRJNA1045289 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26949789_1.fastq.gz	Fastqsanger.gz
	SRR26949789_2.fastq.gz	Fastqsanger.gz
	SRR26949790_1.fastq.gz	Fastqsanger.gz
	SRR26949790_2.fastq.gz	Fastqsanger.gz
	SRR26949791_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [CHIP-seq]

Project description:Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify novel drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV-825, from which we identified anti-cancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the two inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key regulators PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single agent inhibition of either BET or mTOR. Our results tied together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

2024-02-01 | GSE248633 | GEO

CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [RNA-seq]

2024-02-01 | GSE248632 | GEO

CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [RNA-seq]

Project description:CRISPR screening identifies synergy between BET and mTOR inhibitors in cholangiocarcinoma through impaired serine glycine one carbon metabolism [RNA-seq]

| PRJNA1045286 | ENA

CRISPR screening identifies BET and mTOR inhibitor synergy in cholangiocarcinoma through serine glycine one carbon.

Project description:Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged on H3K27ac-marked epigenetic suppression of the serine glycine one carbon (SGOC) metabolism pathway, including the key enzymes PHGDH and PSAT1. Knockdown of PSAT1 was sufficient to replicate synergy with single-agent inhibition of either BET or mTOR. Our results tie together epigenetic regulation, metabolism, and apoptosis induction as key therapeutic targets for further exploration in this underserved disease.

| S-EPMC10906219 | biostudies-literature

D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

Project description:D-Serine, a long-term undetected enantiomer of serine1,2, is a novel biomarker that reflects kidney function and disease activity3-5 and has unclear physiological functions. Here we show that D-serine is a physiological molecule that promotes tissue remodeling and suppresses the onset of diabetes. D-serine is quickly and dominantly distributed to the kidney upon injection in mice, suggesting that the kidney is a key target organ. Unilateral nephrectomy in human living kidney donors decreases urinary excretion and thus increases the blood level of D-serine, which in turn promotes the compensatory enlargement of the remnant kidney in mouse model. D-Serine activates cell cycle for tissue remodeling through an mTOR-related pathway, which promotes metabolic reprograming to glycolytic activation. In rodent diabetic model, D-serine promotes glycolysis in the kidney and suppresses the surge of blood glucose levels. D-Serine has physiological activity that influences kidney function and maintains metabolic homeostasis to reduce diabetic propensity.

2022-04-07 | GSE155475 | GEO

mTOR

Project description:mTOR

| PRJEB9498 | ENA

D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

Project description:D-Serine activates glycolysis via mTOR pathway in kidney remodeling and suppresses onset of diabetes

| PRJNA649903 | ENA

Phosphoglycerate mutase regulates Treg differentiation through control of serine synthesis and one-carbon metabolism

Project description:The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3PG), the PGAM substrate, to de novo serine synthesis. Blocking de novo serine synthesis from 3PG reversed the effect of PGAM inhibition on Treg polarization, while exogenous serine directly inhibited Treg polarization. Addi-tionally, altering serine levels in vivo with a serine/glycine-free diet increased peripheral Tregs and at-tenuated autoimmunity in a murine model of multiple sclerosis. Mechanistically, we found that serine limits Treg polarization by contributing to one-carbon metabolism and methylation of Treg-associated genes. Inhibiting one-carbon metabolism increased Treg polarization and suppressive function both in vitro and in vivo in a murine model of autoimmune colitis. Our study identifies a novel physiologic role for PGAM and highlights the metabolic interconnectivity between glycolysis, serine synthesis, one-car-bon metabolism, and epigenetic regulation of Treg differentiation and suppressive function

2025-06-06 | GSE269846 | GEO

BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma.

Project description:Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver cancer, is a fatal malignancy with a poor prognosis and only very limited therapeutic options. Although molecular targeted therapy is emerged as a promising treatment strategy, resistance to molecular-targeted therapy occurs inevitably, which represents a major clinical challenge. In this study, we confirmed that mammalian target of rapamycin (mTOR) signaling is the most significantly affected pathways in ICC. As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway. We generate the orthotopic ICC mouse model through hydrodynamic transfection of AKT and yes-associated protein (YAP) plasmids into the mouse liver. Our study confirmed that BEZ235 can suppress the proliferation, invasion and colony conformation abilities of ICC cells in vitro but cannot effectively inhibit ICC progression in vivo. Inhibition of PI3K/mTOR allowed upregulation of c-Myc and YAP through suppressed the phosphorylation of LATS1. It would be a novel mechanism that mediated resistance to PI3K/mTOR dual inhibitor. However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors. The efficacy results of combination therapy exhibited effective treatment on ICC in vitro and in vivo. Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.

| S-EPMC8556340 | biostudies-literature

Cholangiocarcinoma tissues VS. corresponding normal bile duct tissues

Project description:To identify miRNAs differentially expressed in cholangiocarcinoma,3 human cholangiocarcinoma and their corresponding normal bile duct tissues were obtained from 3 patients after operation with postoperative pathological diagnosed perihilar or distal biliary cholangiocarcinoma miRNAs expression in human cholangiocarcinoma/normal bile duct samples was measured after operation.Three independent experiments were performed using different patients for each experiment.

2013-06-10 | E-GEOD-47764 | biostudies-arrayexpress

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