https://doi.org/10.1016/j.apsb.2025.04.018
This new article publication from Acta Pharmaceutica Sinica B, discusses how ALKBH3-regulated m1A of ALDOA potentiates glycolysis and doxorubicin resistance of triple negative breast cancer cells.
Chemotherapy is currently the mainstay of systemic management for triple-negative breast cancer (TNBC), but chemoresistance significantly impacts patient outcomes.
This research indicates that Doxorubicin (Dox)-resistant TNBC cells exhibit increased glycolysis and ATP generation compared to their parental cells, with this metabolic shift contributing to chemoresistance. It was discovered that ALKBH3, an m1A demethylase enzyme, is crucial in regulating the enhanced glycolysis in Dox-resistant TNBC cells.
Knocking down ALKBH3 reduced ATP generation, glucose consumption, and lactate production, implicating its involvement in mediating glycolysis. Further investigation revealed that aldolase A (ALDOA), a key enzyme in glycolysis, is a downstream target of ALKBH3. ALKBH3 regulates ALDOA mRNA stability through m1A demethylation at the 3′-untranslated region (3′UTR). This methylation negatively affects ALDOA mRNA stability by recruiting the YTHDF2/PAN2–PAN3 complex, leading to mRNA degradation. The ALKBH3/ALDOA axis promotes Dox resistance both in vitro and in vivo.
Clinical analysis demonstrated that ALKBH3 and ALDOA are upregulated in breast cancer tissues, and higher expression of these proteins is associated with reduced overall survival in TNBC patients. This study highlights the role of the ALKBH3/ALDOA axis in contributing to Dox resistance in TNBC cells through regulation of ALDOA mRNA stability and glycolysis.
Keywords: Glycolysis, Chemoresistance, ALKBH3, m1A, ALDOA, Stability, TNBC, 3′UTR
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525002758-ga1_lrg.jpg
This study reports that ALKBH3 regulates glycolysis in doxorubicin-resistant TNBC cells through m1A methylation of ALDOA mRNA. Specifically, m1A methylation negatively regulated ALDOA mRNA stability by recruiting the YTHDF2/PAN2–PAN3 complex.
