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HEXIM1 is induced by DHODH inhibition to suppress melanoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE57432 | GEO | 2016/04/08

SECONDARY ACCESSION(S): PRJNA246457

REPOSITORIES: GEO

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HEXIM1 is induced by DHODH inhibition to suppress melanoma [ChIP-Seq]

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.

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HEXIM1 is induced by DHODH inhibition to suppress melanoma [Gro-Seq]

2016-04-08 | GSE57430 | GEO

HEXIM1 is induced by DHODH inhibition to suppress melanoma

Project description:HEXIM1 is induced by DHODH inhibition to suppress melanoma

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Nucleotide stress induction of HEXIM1 suppresses melanoma by modulating cancer cell-specific gene transcription