The GCN5L2-SIX1 complex drives glycolysis to promote progression of triple-negative breast cancer.

Lactylation, a lactate-dependent posttranslational modification, is involved in cancer development. Here, we showed that GCN5L2 physically interacts with nuclear SIX1 and acts as a key regulator of SIX1 lactylation. GCN5L2 depletion promotes APC/Cdh1 binding to SIX1, increases SIX1 ubiquitination, and reduces SIX1 protein stability. Functionally, the GCN5L2-SIX1 axis promotes glucose uptake, glycolysis process, and energy supply in TNBC cells. GCN5L2 knockdown attenuates the growth and migration of TNBC cells, and increases the sensitivity of TNBC cells to paclitaxel. Overexpression of SIX1 reverses the GCN5L2 knockdown-induced glycolysis and growth suppression in TNBC cells. In addition, GCN5L2 expression is enriched and positively correlated with SIX1 in clinical TNBC tissues. More importantly, we demonstrated 9‴-Methyl salvianolate B as a candidate modulator of the GCN5L2-SIX1 complex via an unbiased screening. 9‴-Methyl salvianolate B suppresses the GCN5L2-SIX1 axis and blocks the glycolysis, proliferation, metastasis, and paclitaxel resistance of TNBC cells. Overall, this study highlights the significance of the GCN5L2-SIX1 axis in sustaining glycolysis and TNBC development, and provides experimental evidence of 9‴-Methyl salvianolate B as a candidate modulator of the GCN5L2-SIX1 axis, presenting a promising strategy for TNBC management.