The tumor vs. normal (TN), Gleason score (GS) > 7 vs. GS < 7, pathological T stage (pT) = 2 vs. pT = 3, and TP53 mutation vs. wild-type comparisons using TCGA-PRAD dataset revealed 3 intersecting HLM regulators (EZH2, NSD2, and KMT5C) that were consistently upregulated in advanced PCa (GS > 7, pT3, HR > 1, and TP53 mutation) (P < 0.05) and verified in clinical PCa tissues. Here, NSD2 is linked to neoplasm.