Comparative Acetylation and Ubiquitination Profiling in Cervical Cancer-Cell Models Supports a Proposed Lysine-Fate Code

Post-translational modifications are rarely studied as an integrated system. Most studies have focused on acetylation or ubiquitination in isolation, despite both frequently targeting the same lysine residues on the same proteins. This study investigated whether the interplay between these modifications, rather than their individual effects, constitutes a meaningful regulatory layer in cervical cancer cells. Quantitative stoichiometric proteomics was applied to HPV-positive and HPV-negative cell models, with a non-cancerous keratinocyte cell line serving as the control. The results demonstrate that acetylation and ubiquitination form coordinated, context-dependent patterns rather than acting independently. In HPV-positive cells acetylation predominated and was enriched in transcriptional regulators. Conversely, the HPV-negative C33A line exhibited a substantially larger ubiquitinome, indicative of increased proteostatic surveillance. Site-specific stoichiometry analysis revealed that the relative occupancy of each modification at shared lysine residues determines regulatory outcomes, rather than their mere presence. This competition is proposed to constitute a “lysine-fate code” that integrates transcriptional regulation, metabolic adaptation, and immune signaling into a unified proteostatic logic. Beyond their implications for cervical cancer biology, these findings suggest that the acetylation–ubiquitination balance may represent a key regulatory principle. Targeting enzymes that modulate this balance could provide novel therapeutic strategies that surpass single-pathway inhibition.