Clinical epigenetics · 2026
GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.
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Müller Janina, Sofyali Emre, Schwarzmüller Luisa, Aylon Yael, Weizman Eviatar, Schlicker Lisa, Kelly Katherine, Borgoni Simone, Oz Simin, Stocker Cole, Burmester Sara, Wörner Angelika, Karolus Sabine, Michels Birgitta E, Heiss Daniela, Will Rainer, de Melo Costa Veronica Rodrigues, Lutsik Pavlo, Weichenhan Dieter, Hofmann Ilse, Nataraj Nishanth Belugali, Yarden Yosef, Magnani Luca, Plass Christoph, Schulze Almut, Körner Cindy, Oren Moshe, Wiemann Stefan
Аннотация
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.
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.