Abstract
BackgroundThe Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. Recent data have identified new functions of STAT1 associated with tumourigenesis and resistance to genotoxic stress, including ionizing radiation (IR) and chemotherapy. To investigate the mechanisms contributing to the tumourigenic functions of STAT1, we performed a combined transcriptomic-proteomic expressional analysis and found that STAT1 is associated with regulation of energy metabolism with potential implication in the Warburg effect.MethodsWe generated a stable knockdown of STAT1 in the SCC61 human squamous cell carcinoma cell line, established tumour xenografts in athymic mice, and compared transcriptomic and proteomic profiles of STAT1 wild-type (WT) and knockdown (KD) untreated or irradiated (IR) tumours. Transcriptional profiling was based on Affymetrix Human GeneChip® Gene 1.0 ST microarrays. Proteomes were determined from the tandem mass spectrometry (MS/MS) data by searching against the human subset of the UniProt database. Data were analysed using Significance Analysis of Microarrays for ribonucleic acid and Visualize software for proteins. Functional analysis was performed with Ingenuity Pathway Analysis with statistical significance measured by Fisher's exact test.ResultsKnockdown of STAT1 led to significant growth suppression in untreated tumours and radio sensitization of irradiated tumours. These changes were accompanied by alterations in the expression of genes and proteins of glycolysis/gluconeogenesis (GG), the citrate cycle (CC) and oxidative phosphorylation (OP). Of these pathways, GG had the most concordant changes in gene and protein expression and demonstrated a STAT1-dependent expression of genes and proteins consistent with tumour-specific glycolysis. In addition, IR drastically suppressed the GG pathway in STAT1 KD tumours without significant change in STAT1 WT tumours.ConclusionOur results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes. STAT1-dependent expressional regulation of glycolysis suggests a potential role for STAT1 as a transcriptional modulator of genes responsible for the Warburg effect.
Highlights
The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor
Our results identify a previously uncharacterized function of STAT1 in tumours: expressional regulation of genes encoding proteins involved in glycolysis, the citrate cycle and mitochondrial oxidative phosphorylation, with predominant regulation of glycolytic genes
Our results demonstrate that STAT1 modulates the expression of genes encoding proteins involved in glycolysis/gluconeogenesis (GG), oxidative phosphorylation (OP), and the citrate cycle (CC) and protects against ionizing radiation (IR)-induced suppression of genes and proteins belonging to these pathways
Summary
The Signal Transducer and Activator of Transcription 1 (STAT1) has traditionally been regarded as a transmitter of interferon signaling and a pro-apoptotic tumour suppressor. While STAT1 has traditionally been regarded as pro-apoptotic and tumour-suppressing [1,2], we previously demonstrated that overexpression of the STAT1 pathway confers radio resistance and IFN-resistance [3,4,5]. Consistent with our observations are recent reports demonstrating that constitutive over-expression of STAT1 and STAT1-dependent genes is associated with protection of tumour cells from genotoxic stress following treatment with fludarabine [6], doxorubicin [7], cisplatin [8] and the combination of ionizing radiation (IR) and doxorubicin [9,10]. To investigate the mechanisms by which STAT1 confers an aggressive tumour phenotype, we characterized the downstream pathways regulated by STAT1 To this end, we generated a stable STAT1 knockdown (KD) in SCC61, a clinically derived squamous cell carcinoma cell line [3,4], and studied the effect of STAT1 KD on tumour growth and response to IR in vivo. Our results are consistent with Warburg's finding that tumour cells utilize glycolysis as the main pathway of energy metabolism even in the presence of oxygen [11] and suggest that STAT1 is involved in the transcriptional regulation of the Warburg effect in tumour cells
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