Our studies with in vitro and in vivo evidence added valuable knowledge to decode this phenomenon in 3 ways: 1) Skp2 ablation results in a reduction of H3K4 trimethylation and a suppression of cancer progression; 2) JARID1B activity requires its K63-linked ubiquitination, which is suppressed by elevated SKP2 through regulating E3 ubiquitin ligase TRAF6 in PCa cells; and 3) K63-linked ubiquitination of JARID1B may be required for protein trafficking into nucleolus to control cellular homeostasis through senescence mechanism. Here, KDM5B is linked to cancer.