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MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

ABSTRACT: MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

PROVIDER: PRJNA508498 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8282920.fastq.gz	Fastqsanger.gz
	SRR8282921.fastq.gz	Fastqsanger.gz
	SRR8282922.fastq.gz	Fastqsanger.gz

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MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

Project description:MYC, together with Cohesin and Mediator complexes, predetermines the sensitivity of gastrointestinal cancer to antifolate drugs

2019-11-19 | GSE123364 | GEO

MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription

Project description:MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription

| PRJNA564940 | ENA

MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription.

Project description:BACKGROUND:Thymidylate synthase (TYMS) is a successful chemotherapeutic target for anticancer therapy. Numerous TYMS inhibitors have been developed and used for treating gastrointestinal cancer now, but they have limited clinical benefits due to the prevalent unresponsiveness and toxicity. It is urgent to identify a predictive biomarker to guide the precise clinical use of TYMS inhibitors. METHODS:Genome-scale CRISPR-Cas9 knockout screening was performed to identify potential therapeutic targets for treating gastrointestinal tumours as well as key regulators of raltitrexed (RTX) sensitivity. Cell-based functional assays were used to investigate how MYC regulates TYMS transcription. Cancer patient data were used to verify the correlation between drug response and MYC and/or TYMS mRNA levels. Finally, the role of NIPBL inactivation in gastrointestinal cancer was evaluated in vitro and in vivo. FINDINGS:TYMS is essential for maintaining the viability of gastrointestinal cancer cells, and is selectively inhibited by RTX. Mechanistically, MYC presets gastrointestinal cancer sensitivity to RTX through upregulating TYMS transcription, supported by TCGA data showing that complete response cases to TYMS inhibitors had significantly higher MYC and TYMS mRNA levels than those of progressive diseases. NIPBL inactivation decreases the therapeutic responses of gastrointestinal cancer to RTX through blocking MYC. INTERPRETATION:Our study unveils a mechanism of how TYMS is transcriptionally regulated by MYC, and provides rationales for the precise use of TYMS inhibitors in the clinic. FUNDING:This work was financially supported by grants of NKRDP (2016YFC1302400), STCSM (16JC1406200), NSFC (81872890, 81322034, 81372346) and CAS (QYZDB-SSW-SMC034, XDA12020210).

| S-EPMC6838448 | biostudies-literature

MYC predetermines the sensitivity of gastrointestinal cancer to antifolate drugs through regulating TYMS transcription

Project description:The goal of this study is to dig out the downstream gnens of NIPBL

2019-11-19 | GSE137253 | GEO

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Project description:Thermal Proteome Profiling (TPP) allows for identification of drug (off-)targets by evaluating shifts in apparent melting temperature for proteins. In this study, we use TPP to identify the targets for a novel antifolate (C1).

2023-08-08 | PXD040155 | Pride

The antifolate pemetrexed induces innate tolerance in human macrophages

Project description:The antifolate pemetrexed induces innate tolerance in human macrophages

| PRJNA668719 | ENA

Crystallographic and molecular-orbital studies on the geometry of antifolate drugs.

Project description:In the common dihydrofolate reductase inhibitors an amino substituent replaces the pteridine carbonyl oxygen atom of folates, with altered hydrogen-bonding properties and size. Flexibility in the amino groups could facilitate enzyme binding. Studies of cycloguanil hydrochloride by neutron diffraction show both in-plane and out-of-plane deformation of amino groups. Molecular-orbital calculations ab initio on 2,4-diamino-5-methylpyrimidinium cation confirm that the 4-amino group is readily deformable. The 2,4-diaminoquinazoline structure is reported. Atomic co-ordinates, thermal parameters, bond distances and bond angles for cycloguanil and 2,4-diaminoquinazoline have been deposited as Supplementary Publication SUP 50108 (13 pages) at the British Library Lending Division, Boston Spa. Wetherby, West Yorkshire LS23, 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1978) 169, 5.

| S-EPMC1161822 | biostudies-other

The role of the antifolate methotrexate in LPS response in human macrophages

Project description:The role of the antifolate methotrexate in LPS response in human macrophages

| PRJNA784296 | ENA

Differential chemosensitivity to antifolate drugs between RAS and BRAF melanoma cells.

Project description:BackgroundThe importance of the genetic background of cancer cells for the individual susceptibility to cancer treatments is increasingly apparent. In melanoma, the existence of a BRAF mutation is a main predictor for successful BRAF-targeted therapy. However, despite initial successes with these therapies, patients relapse within a year and have to move on to other therapies. Moreover, patients harbouring a wild type BRAF gene (including 25% with NRAS mutations) still require alternative treatment such as chemotherapy. Multiple genetic parameters have been associated with response to chemotherapy, but despite their high frequency in melanoma nothing is known about the impact of BRAF or NRAS mutations on the response to chemotherapeutic agents.MethodsUsing cell proliferation and DNA methylation assays, FACS analysis and quantitative-RT-PCR we have characterised the response of a panel of NRAS and BRAF mutant melanoma cell lines to various chemotherapy drugs, amongst them dacarbazine (DTIC) and temozolomide (TMZ) and DNA synthesis inhibitors.ResultsAlthough both, DTIC and TMZ act as alkylating agents through the same intermediate, NRAS and BRAF mutant cells responded differentially only to DTIC. Further analysis revealed that the growth-inhibitory effects mediated by DTIC were rather due to interference with nucleotide salvaging, and that NRAS mutant melanoma cells exhibit higher activity of the nucleotide synthesis enzymes IMPDH and TK1. Importantly, the enhanced ability of RAS mutant cells to use nucleotide salvaging resulted in resistance to DHFR inhibitors.ConclusionIn summary, our data suggest that the genetic background in melanoma cells influences the response to inhibitors blocking de novo DNA synthesis, and that defining the RAS mutation status could be used to stratify patients for the use of antifolate drugs.

| S-EPMC4079649 | biostudies-literature

CTCF-mediated 3D chromatin predetermines the gene expression program in the male germline (Hi-C)

Project description:Spermatogenesis is a unidirectional differentiation process to produce haploid sperm. However, it remains largely unknown how the gene expression program is determined to direct a unidirectional differentiation. Here we unveil the high-resolution 3D chromatin architecture of male germ cells and show that CTCF-mediated 3D chromatin predetermines the gene expression program required for spermatogenesis. At the mitosis-to-meiosis transition, the germline-specific Polycomb protein SCML2 resolves chromatin loops specific to mitotic spermatogonia. On autosomes, CTCF-mediated 3D chromatin manifests the structural feature of meiosis-specific super-enhancer (meiotic SE) loci already in undifferentiated spermatogonia. In meiotic spermatocytes, the master transcription factor A-MYB is recruited to these meiotic SE loci to strengthen their 3D contacts to instruct the burst of meiotic gene expression. Further, SCML2 and A-MYB establish unique 3D chromatin of the sex chromosomes in meiotic sex chromosome inactivation. We propose that CTCF-mediated 3D chromatin underlines epigenetic priming to direct unidirectional differentiation, thereby determining the cellular identity of the male germline.

2024-12-13 | GSE244676 | GEO

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