Integrated Pan-Cancer Analysis and Functional Characterization of ATPSCKMT in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) remains a major cause of cancer mortality, highlighting the need to identify functionally relevant molecular determinants. We systematically evaluated 38 genes classified as members of the methyltransferase-like (METTL) family and/or seven-β-strand lysine methyltransferases using pan-cancer genomic, transcriptomic, survival, and dependency datasets, followed by functional assessment in HCC cell lines. Integrated analysis prioritized ATP synthase c-subunit lysine methyltransferase (ATPSCKMT) for investigation in liver hepatocellular carcinoma (LIHC), where elevated expression was associated with adverse prognosis. DEMETER2 analysis also identified widespread RNAi dependency across cancer types. siRNA-mediated ATPSCKMT knockdown in JHH7 and HEP3B cells reduced CCK-8 signals and EdU incorporation. Network and co-expression analyses identified CCT5 as a representative ATPSCKMT-associated candidate, with reproducible positive correlations across independent HCC cohorts. In TCGA-LIHC, the ATPSCKMT–CCT5 correlation persisted after adjustment for shared local copy-number variation (partial Spearman ρ = 0.522). Single-cell analysis of primary HCC malignant hepatocytes further revealed patient-level co-detection, although these findings may be influenced by differences in transcript detection. Overall, our findings support further investigation of ATPSCKMT in HCC proliferation-associated phenotypes and identify CCT5 as a reproducible co-expression candidate.