A cancer-specific antigen drives histone acetylation by stabilizing the acetyltransferases

Histone acetylation is a critical modification that regulates gene expression by modulating chromatin structure and function. Histone acetyltransferases are essential for maintaining acetylation homeostasis, and the disruption of this balance can lead to aberrant gene expression and cancer development. Here, we describe that the cancer-specific protein MAGE-A10 increases cellular histone acetylation by stabilizing essential histone acetyltransferases KAT2A and KAT2B. The aberrant expression of MAGE-A10 in tumors prevents the degradation of KAT2A/2B through p62-mediated autophagy. Mechanistically, MAGE-A10 antagonizes the binding of KAT2A/2B with the E3 ubiquitin ligase complex CUL4A-DDB1, thereby decreasing the formation of their K63-linked ubiquitination. Furthermore, KAT2A enhances the transcription of the MAGE-A10 gene, forming a positive feedback loop that contributes to tumorigenesis. These findings provide insights into the molecular mechanisms hijacked in cancer that drive perturbed histone acetylation and suggest potential therapeutic strategies.