GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.
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.
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.
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.
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.
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.
Authors
Müller Müller, Sofyali Sofyali, Schwarzmüller Schwarzmüller, Aylon Aylon, Weizman Weizman, Schlicker Schlicker, Kelly Kelly, Borgoni Borgoni, Oz Oz, Stocker Stocker, Burmester Burmester, Wörner Wörner, Karolus Karolus, Michels Michels, Heiss Heiss, Will Will, de Melo Costa de Melo Costa, Lutsik Lutsik, Weichenhan Weichenhan, Hofmann Hofmann, Nataraj Nataraj, Yarden Yarden, Magnani Magnani, Plass Plass, Schulze Schulze, Körner Körner, Oren Oren, Wiemann Wiemann
View on Pubmed