HEXIM1 is induced by DHODH inhibition to suppress melanoma
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA246457 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR1275490.fastq.gz | Fastqsanger.gz | |||
| SRR1275500.fastq.gz | Fastqsanger.gz | |||
| SRR1275491.fastq.gz | Fastqsanger.gz | |||
| SRR1275501.fastq.gz | Fastqsanger.gz | |||
| SRR1275492.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 18 |
Similar Datasets
Project description:Recent evidence suggests that leflunomide, a DHODH inhibitor, disrupts neural crest development and melanoma pathogenesis via inhibiting transcription elongation. Here, we provide evidence that a transcriptional regulator, HEXIM1, is upregulated in response to leflunomide. HEXIM1 is assembled into the 7SK snRNP complex to sequester and inhibit the kinase P-TEFb. P-TEFb triggers elongation by phosphorylating RNA polymerase II and pausing factors. Knockdown of hexim in zebrafish rescues the effects of leflunomide. HEXIM1 expression is low in human melanoma. In addition, HEXIM1 overexpression can suppress melanoma onset in zebrafish. Increased HEXIM1 expression, in response to low nucleotides triggered by DHODH inhibition, sequesters P-TEFb away from melanoma pathogenesis, proliferation and cell cycle genes based on GRO-seq and ChIP-seq analyses. This reduces productive elongation at genes that maintain the tumorigenic state. Our study illustrates that HEXIM1 is a tumor suppressor that responds to cell stress, consequently inhibiting productive elongation of proliferative genes in melanoma.
2016-04-08 | GSE57431 | GEO
Project description:Recent evidence suggests that leflunomide, a DHODH inhibitor, disrupts neural crest development and melanoma pathogenesis via inhibiting transcription elongation. Here, we provide evidence that a transcriptional regulator, HEXIM1, is upregulated in response to leflunomide. HEXIM1 is assembled into the 7SK snRNP complex to sequester and inhibit the kinase P-TEFb. P-TEFb triggers elongation by phosphorylating RNA polymerase II and pausing factors. Knockdown of hexim in zebrafish rescues the effects of leflunomide. HEXIM1 expression is low in human melanoma. In addition, HEXIM1 overexpression can suppress melanoma onset in zebrafish. Increased HEXIM1 expression, in response to low nucleotides triggered by DHODH inhibition, sequesters P-TEFb away from melanoma pathogenesis, proliferation and cell cycle genes based on GRO-seq and ChIP-seq analyses. This reduces productive elongation at genes that maintain the tumorigenic state. Our study illustrates that HEXIM1 is a tumor suppressor that responds to cell stress, consequently inhibiting productive elongation of proliferative genes in melanoma.
2016-04-08 | GSE57430 | GEO
Project description:HEXIM1 is induced by DHODH inhibition to suppress melanoma [ChIP-Seq]
| PRJNA246458 | ENA
Project description:HEXIM1 is induced by DHODH inhibition to suppress melanoma [Gro-Seq]
| PRJNA246459 | ENA
Project description:This study investigates the transcriptional consequences of genetic and pharmacological DHODH inhibition in PIK3CA-mutant colorectal cancer. RNA sequencing was performed in RKO cells following either DHODH knockdown (shDHODH versus shNT) or treatment with the DHODH inhibitor HL6 (HL6 versus DMSO) to characterize the transcriptional programs regulated by DHODH and compare the effects of genetic and pharmacological inhibition.
2026-06-19 | GSE335693 | GEO
Project description:Dihydroorotate dehydrogenase (DHODH), a key enzyme in de novo pyrimidine biosynthesis, has recently emerged as a therapeutic target in various cancers. We have previously identified a pivotal role of DHODH in initiation of cutaneous squamous cell carcinoma (cSCC), the second most common type of non-melanoma skin cancer. However, the key mechanisms driving the anticancer activity of DHODH inhibition remain unexplored in cSCC. To evaluate the impact of DHODH inhibition on cSCC growth, we employed three complementary approaches: (1) pharmacological inhibition of DHODH in mice bearing xenografts of A431 and SCC13 cells through oral administration of leflunomid (LFN) or PTC299 (PTC), and (2) genetic silencing of DHODH via transduction of cells with a lentiviral vector expressing shRNA targeting DHODH (shDHODH) prior to transplantation into NSG mice. After transplantation of A431 or SCC13 cells and once tumors reached an average volume of 150 to 200 mm3, mice were divided into two groups that receiving either vehicle alone or LFN administrated orally on a daily basis. The same procedure was applied for treatment with PTC299. To further investigate, DHODH expression was downregulated in A431 and SCC13 cells using shDHODH. Cells transduced with shCtrol used as control. Six days after transduction, the cells were subcutaneously engrafted into NSG mice. To investigate the molecular consequences of DHODH inhibition across distinct cSCC models, label-free quantitative proteomic analyses were performed on A431 and SCC13 xenografts treated with LFN or PTC299, as well as on tumors transduced with shDHODH (6 xenografts per group).
2026-06-15 | PXD070860 | Pride
Project description:This SuperSeries is composed of the SubSeries listed below.
2016-04-08 | GSE57432 | GEO
Project description:Cancer metabolism has been actively studied to gain insights into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a novel melanoma suppressor that participates in nucleotide stress regulation. HEXIM1 expression is low in melanoma. Its overexpression suppresses melanoma while its inactivation accelerates tumor onset in vivo. HEXIM1 responds to nucleotide stress. Knockdown of HEXIM1 rescues neural crest and melanoma nucleotide stress phenotypes in vivo. Mechanistically, under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to pause transcription at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic transcripts to bind to and be stabilized by HEXIM1. HEXIM1 therefore plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals a novel role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.
2017-01-01 | GSE68045 | GEO
Project description:Cancer metabolism has been actively studied to gain insights into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a novel melanoma suppressor that participates in nucleotide stress regulation. HEXIM1 expression is low in melanoma. Its overexpression suppresses melanoma while its inactivation accelerates tumor onset in vivo. HEXIM1 responds to nucleotide stress. Knockdown of HEXIM1 rescues neural crest and melanoma nucleotide stress phenotypes in vivo. Mechanistically, under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to pause transcription at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic transcripts to bind to and be stabilized by HEXIM1. HEXIM1 therefore plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals a novel role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.
2017-01-01 | GSE68044 | GEO
Project description:Cancer metabolism has been actively studied to gain insights into tumorigenic survival mechanisms and susceptibilities. In melanoma, we identify HEXIM1, a transcription elongation regulator, as a novel melanoma suppressor that participates in nucleotide stress regulation. HEXIM1 expression is low in melanoma. Its overexpression suppresses melanoma while its inactivation accelerates tumor onset in vivo. HEXIM1 responds to nucleotide stress. Knockdown of HEXIM1 rescues neural crest and melanoma nucleotide stress phenotypes in vivo. Mechanistically, under nucleotide stress, HEXIM1 is induced to form an inhibitory complex with P-TEFb, the kinase that initiates transcription elongation, to pause transcription at tumorigenic genes. The resulting alteration in gene expression also causes anti-tumorigenic transcripts to bind to and be stabilized by HEXIM1. HEXIM1 therefore plays an important role in inhibiting cancer cell-specific gene transcription while also facilitating anti-cancer gene expression. Our study reveals a novel role for HEXIM1 in coupling nucleotide metabolism with transcriptional regulation in melanoma.
2017-01-01 | GSE68040 | GEO