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GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer
Janina Müller1,2, Emre Sofyali1,2, Luisa Schwarzmüller1,2
1Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Background:
Estrogen receptor alpha (ERα)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success.
Results:
We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling, however, independently of estrogen.
Conclusions:
These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.
Insights
Glycine-N-Acyltransferase Like 1 (GLYATL1) drives resistance to aromatase inhibitor (AI) therapy in ER-positive breast cancer by altering metabolism and epigenetics. Targeting GLYATL1 may overcome this resistance, improving patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Metabolic Research
Background:
- Estrogen receptor alpha (ERα)-positive luminal breast cancer treatment relies on aromatase inhibitors (AI) to block estrogen signaling.
- Therapeutic resistance to AI frequently develops, limiting treatment efficacy.
Purpose of the Study:
- To investigate the role of GLYATL1 in AI resistance.
- To explore GLYATL1 as a potential therapeutic target for overcoming endocrine therapy resistance.
Main Methods:
- Analysis of GLYATL1 expression in AI-resistant breast cancer models and patient samples.
- Functional studies involving GLYATL1 knockdown or knockout.
- Assessment of succinate levels and epigenetic histone marks.
- Evaluation of cell proliferation under estrogen-deprived conditions.
Main Results:
- GLYATL1 expression is upregulated in AI-resistant breast cancer and correlates with poorer survival.
- GLYATL1 promotes estrogen deprivation resistance by increasing succinate and altering epigenetic marks.
- GLYATL1 regulates proliferation under estrogen deprivation.
- GLYATL1 expression is positively regulated by ERα signaling, independent of estrogen.
Conclusions:
- GLYATL1 acts as a metabolic and epigenetic mediator of endocrine therapy resistance.
- GLYATL1 is a potential therapeutic target to overcome AI resistance in luminal breast cancer.
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