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Published on: October 10, 2020
The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to
Michael J Lukey1, Kai Su Greene1, Jon W Erickson2
1Department 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.
Insights
The transcription factor c-Jun drives cancer cell metabolism by increasing glutaminase (GLS) levels. Cancers with high c-Jun may benefit from GLS-targeted therapies.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Transformed cells display altered glucose metabolism and increased glutamine utilization for growth and energy.
- These metabolic shifts during tumorigenesis are controlled by oncogenic signals.
Purpose of the Study:
- To investigate the role of transcription factor c-Jun in regulating cancer cell metabolism, specifically glutamine utilization.
- To determine if c-Jun influences mitochondrial glutaminase (GLS) levels and activity.
Main Methods:
- Investigated c-Jun's regulation of GLS gene expression and activity in human breast cancer cells.
- Analyzed the direct binding of c-Jun to the GLS promoter region using molecular biology techniques.
- Assessed the impact of c-Jun overexpression on breast cancer cell dependence on GLS activity.
Main Results:
- c-Jun directly binds to the GLS promoter, increasing gene expression and glutaminase activity.
- Elevated GLS protein levels and sensitivity to GLS inhibition in breast cancer cells correlate with c-Jun levels.
- Overexpression of c-Jun leads to increased dependence of cancer cells on GLS activity.
Conclusions:
- c-Jun is a key regulator of mitochondrial glutaminase (GLS) and a driver of cancer cell metabolic reprogramming.
- Cancers with high JUN expression may be particularly responsive to therapies targeting GLS.
