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The aryl hydrocarbon receptor regulates nucleolar activity and protein synthesis in MYC-expressing cells

ABSTRACT: MYC enhances protein synthesis by regulating genes involved in ribosome biogenesis and protein translation. Here, we show that MYC-induced protein translation is mediated by the transcription factor aryl hydrocarbon receptor (AHR), which is induced by MYC in colonic cells. AHR promotes protein synthesis by activating the transcription of genes required for ribosome biogenesis and protein translation, including OGFOD1 and NOLC1. Using surface sensing of translation (SUnSET) to measure global protein translation, we found that silencing AHR or its targets diminishes protein synthesis. Therefore, targeting AHR or its downstream pathways could provide a novel approach to limit biomass production in MYC-driven tumors.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE135061 | GEO | 2019/07/30

REPOSITORIES: GEO

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Transcriptional Regulation of Protein Synthesis by Mediator Kinase Represents a Therapeutic Vulnerability in MYC-driven Medulloblastoma

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OGFOD1 Regulates Translation to Alter Hypertrophy Susceptibility

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Project description:Levels of the ribosome, the conserved molecular machine that mediates translation, are tightly linked to cellular growth rate. In humans, ribosomopathies are diseases associated with cell-type-specific pathologies and reduced ribosomal protein (RP) levels. Because gene expression defects resulting from ribosome deficiency have not yet been experimentally defined, we systematically probed mRNA, translation, and protein signatures that were either unlinked or linked to cellular growth rate in RP-deficient yeast cells. Ribosome concentration was seen to be associated with translation of gene sub-classes, and profound general secondary effects of RP loss on the spectrum of cellular mRNAs were seen. Among these effects, growth-defective 60S mutants increased synthesis of proteins involved in proteasome-mediated degradation, whereas 40S mutants accumulated mature 60S subunits and increased translation of ribosome biogenesis genes. These distinct signatures of protein synthesis suggest intriguing and currently mysterious differences in the cellular consequences of deficiency for small and large ribosomal subunits.

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Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.

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RNA-seq analysis after dBRD9-A treatment in human multiple myeloma cell line OPM2 and H929

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Gene expression profiling of dMyc null Drosophila larvae

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