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The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.

Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA - Nat Commun (2016)

Bottom Line: We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression.Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity.These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

No MeSH data available.


Related in: MedlinePlus

The GLS transcript correlates with established c-Jun target transcripts in invasive breast cancer.Bar chart showing the Spearman correlation coefficients between mRNA levels of GLS and of established c-Jun transcriptional targets. Transcripts that are upregulated by c-Jun are shown in black, and almost exclusively correlate positively with GLS. Transcripts that are repressed by c-Jun are shown in white, and all correlate negatively with GLS. Correlation plots were prepared and correlation coefficients determined using the cBioportal suite of tools and data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set.
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f7: The GLS transcript correlates with established c-Jun target transcripts in invasive breast cancer.Bar chart showing the Spearman correlation coefficients between mRNA levels of GLS and of established c-Jun transcriptional targets. Transcripts that are upregulated by c-Jun are shown in black, and almost exclusively correlate positively with GLS. Transcripts that are repressed by c-Jun are shown in white, and all correlate negatively with GLS. Correlation plots were prepared and correlation coefficients determined using the cBioportal suite of tools and data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set.

Mentions: To establish further the relationship between c-Jun activity and GLS expression in breast cancer, we used the cBioportal4546 suite of tools (www.cbioportal.org) to analyse data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set (959 samples). In many cancers, upregulation of c-Jun occurs at the post-transcriptional and post-translational levels, but not at the transcriptional level (see Discussion). Consequently, JUN mRNA levels are rarely upregulated, even though c-Jun protein levels can be highly elevated. Consistent with these findings, TCGA data showed that JUN mRNA was elevated (z score >2.0) in only 3% of invasive breast carcinoma samples. We therefore determined whether the expression levels of some validated c-Jun transcriptional targets correlate with those of GLS. We selected only confirmed direct targets of c-Jun (and not v-Jun) that contain a c-Jun binding site within the promoter region35474849, and we eliminated from the list those c-Jun target genes that are frequently altered at the genomic level within the data set (for example, CCND1, amplified in 16% of samples, and TP53, mutated in 31% of samples). Using the resulting list of c-Jun targets (Supplementary Table 2), we found that transcripts that are upregulated by c-Jun almost invariably correlate positively with GLS mRNA levels, whereas those targets that are transcriptionally repressed by c-Jun exhibit a negative correlation with the GLS transcript (Fig. 7; see also Supplementary Figs 12 and 13).


The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy.

Lukey MJ, Greene KS, Erickson JW, Wilson KF, Cerione RA - Nat Commun (2016)

The GLS transcript correlates with established c-Jun target transcripts in invasive breast cancer.Bar chart showing the Spearman correlation coefficients between mRNA levels of GLS and of established c-Jun transcriptional targets. Transcripts that are upregulated by c-Jun are shown in black, and almost exclusively correlate positively with GLS. Transcripts that are repressed by c-Jun are shown in white, and all correlate negatively with GLS. Correlation plots were prepared and correlation coefficients determined using the cBioportal suite of tools and data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4837472&req=5

f7: The GLS transcript correlates with established c-Jun target transcripts in invasive breast cancer.Bar chart showing the Spearman correlation coefficients between mRNA levels of GLS and of established c-Jun transcriptional targets. Transcripts that are upregulated by c-Jun are shown in black, and almost exclusively correlate positively with GLS. Transcripts that are repressed by c-Jun are shown in white, and all correlate negatively with GLS. Correlation plots were prepared and correlation coefficients determined using the cBioportal suite of tools and data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set.
Mentions: To establish further the relationship between c-Jun activity and GLS expression in breast cancer, we used the cBioportal4546 suite of tools (www.cbioportal.org) to analyse data from The Cancer Genome Atlas (TCGA) Breast Invasive Carcinoma (TCGA, provisional) data set (959 samples). In many cancers, upregulation of c-Jun occurs at the post-transcriptional and post-translational levels, but not at the transcriptional level (see Discussion). Consequently, JUN mRNA levels are rarely upregulated, even though c-Jun protein levels can be highly elevated. Consistent with these findings, TCGA data showed that JUN mRNA was elevated (z score >2.0) in only 3% of invasive breast carcinoma samples. We therefore determined whether the expression levels of some validated c-Jun transcriptional targets correlate with those of GLS. We selected only confirmed direct targets of c-Jun (and not v-Jun) that contain a c-Jun binding site within the promoter region35474849, and we eliminated from the list those c-Jun target genes that are frequently altered at the genomic level within the data set (for example, CCND1, amplified in 16% of samples, and TP53, mutated in 31% of samples). Using the resulting list of c-Jun targets (Supplementary Table 2), we found that transcripts that are upregulated by c-Jun almost invariably correlate positively with GLS mRNA levels, whereas those targets that are transcriptionally repressed by c-Jun exhibit a negative correlation with the GLS transcript (Fig. 7; see also Supplementary Figs 12 and 13).

Bottom Line: We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression.Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity.These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.

ABSTRACT
Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

No MeSH data available.


Related in: MedlinePlus