Abstract
Lysine deacetylases (KDACs) are central regulators of chromatin organization, transcription, metabolism, DNA repair, and cellular signaling, yet their molecular and clinical landscape across human cancers has not been systematically defined. Here, we performed the first comprehensive pan-cancer characterization of the complete human lysine deacetylase superfamily by integrating transcriptomic, genomic, and clinical datasets across The Cancer Genome Atlas (TCGA). Systematic analyses of all 18 human deacetylases revealed extensive but highly heterogeneous patterns of dysregulation, demonstrating that individual family members exhibit distinct transcriptional profiles, copy-number alterations, mutation frequencies, and prognostic associations despite sharing a common catalytic function. HDAC10 and SIRT6 emerged as the most consistently overexpressed deacetylases, whereas SIRT1 and HDAC4 displayed widespread transcriptional repression. Copy-number analysis identified SIRT7 as the most frequently amplified deacetylase across human malignancies, while survival analysis further demonstrated that elevated SIRT7 expression was associated with adverse clinical outcomes, particularly in kidney renal clear cell carcinoma. Integrative multi-omics prioritization identified SIRT7 as the highest-confidence candidate for mechanistic investigation. Integration of human SIRT7 knockout transcriptomic datasets with TCGA-derived expression profiles identified 204 conserved SIRT7-activated genes and 135 conserved SIRT7-repressed genes, which were significantly enriched for pathways governing cell-cycle progression, chromosome segregation, DNA replication, and genome maintenance. Network-based prioritization further identified PIF1, TROAP, AURKB, KIF18B, CHTF18, PKMYT1, MYBL2, and CDCA3 as central components of a conserved SIRT7-associated regulatory module. Collectively, this study establishes the first comprehensive pan-cancer molecular atlas of the human lysine deacetylase superfamily and demonstrates that deacetylases comprise a functionally diverse network of cancer regulators rather than a homogeneous class of epigenetic enzymes. Beyond prioritizing SIRT7 as a clinically relevant deacetylase linked to genome maintenance and mitotic progression, our integrative analytical framework provides a valuable resource for biomarker discovery, mechanistic investigation, and the development of precision epigenetic therapies.