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Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells

ABSTRACT: Metabolism is tightly coupled with the process of aging, and tumorigenesis. However, the mechanisms regulating metabolic properties in different contexts remain unclear. Cellular senescence is widely recognized as an important tumor suppressor function and accompanies metabolic remodeling characterized by increased mitochondrial oxidative phosphorylation (OXPHOS). Here we showed retinoblastoma (RB) is required for the increased OXPHOS in oncogene-induced senescent (OIS) cells. Combined metabolic and gene expression profiling revealed that RB mediated activation of the glycolytic pathway in OIS cells, causing upregulation of several glycolytic genes and concomitant increases in the levels of associated metabolites in the glycolytic pathway. Knockdown of these genes by small interfering RNAs (siRNAs) resulted in decreased mitochondrial respiration, suggesting that RB-mediated glycolytic gene activation promotes metabolic flux into the OXPHOS pathway. These results suggest that coordinate transcriptional activation of metabolic genes by RB enables OIS cells to maintain metabolically bivalent states that both glycolysis and OXPHOS are highly active. Collectively, our findings demonstrated a previously unrecognized function of RB in OIS cells. To understand the role of RB, we investigated the effect of RB1-knockdown in the transcription profile of oncogene-induced senescent (OIS) cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60652 | GEO | 2015/05/26

SECONDARY ACCESSION(S): PRJNA259203

REPOSITORIES: GEO

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Retinoblastoma protein promotes oxidative phosphorylation through upregulation of glycolytic genes in oncogene-induced senescent cells

Project description:Metabolism is tightly coupled with the process of aging, and tumorigenesis. However, the mechanisms regulating metabolic properties in different contexts remain unclear. Cellular senescence is widely recognized as an important tumor suppressor function and accompanies metabolic remodeling characterized by increased mitochondrial oxidative phosphorylation (OXPHOS). Here we showed retinoblastoma (RB) is required for the increased OXPHOS in oncogene-induced senescent (OIS) cells. Combined metabolic and gene expression profiling revealed that RB mediated activation of the glycolytic pathway in OIS cells, causing upregulation of several glycolytic genes and concomitant increases in the levels of associated metabolites in the glycolytic pathway. Knockdown of these genes by small interfering RNAs (siRNAs) resulted in decreased mitochondrial respiration, suggesting that RB-mediated glycolytic gene activation promotes metabolic flux into the OXPHOS pathway. These results suggest that coordinate transcriptional activation of metabolic genes by RB enables OIS cells to maintain metabolically bivalent states that both glycolysis and OXPHOS are highly active. Collectively, our findings demonstrated a previously unrecognized function of RB in OIS cells. To understand the role of RB, we investigated the effect of RB1-knockdown in the transcription profile of oncogene-induced senescent (OIS) cells. IMR90 ER:Ras cells were treated with 100 nM 4-OHT for 6 days to induce senescence. RNA was isolated 6 days after OHT treatment and hybridized to Affymetrix microarrays. SiRNA transfection (control siRNA or siRB1) was performed 4 days before RNA isolation.

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Mitotic stress is an integral part of the oncogene-induced senescence program that promotes multinucleation and cell cycle arrest

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H3K9me3 ChIPseq experiments from PD IMR90s

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Notch signalling mediates secondary senescence

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Identification of differentially expressed genes between senescence and senescence bypass cells

Project description:We applied RNA-seq analysis to control and senescent human primary BJ fibroblast cells (senescence induced by activation of the oncogenic RASG12V gene), as well as in BJ cells that fully or partially bypass oncogene-idnuced senescence (OIS) due to knock-down of either p53 or BRD7 or LncRNA-OIS1 (using 4 different shRNAs).

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