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The alteration of expression of p16 INK4a , a well-known cyclin-dependent kinase inhibitor involved in cell cycle control, in tumors is unclear, especially under hypoxic conditions. To evaluate p16 INK4a regulation, we performed a protein microarray analysis. Among 1,800 proteins in the array, we identified hYSK1 as a novel protein that interacts with the tumor suppressor p16 INK4a . hYSK1, a member of the Ste20 family of serine/threonine protein kinases, promotes cell migration and tumorigenesis and is activated by oxidative stress. However, the molecular mechanisms underlying the oncogenic potential of hYSK1 remain elusive. Here, we report that hYSK1 interacts with p16 INK4a under hypoxic conditions in tumors, where it negatively regulates p16 INK4a , enhancing cancer cell migration. Hypoxic stimulation of hYSK1 reduces p16 INK4a accumulation through p16 promoter regulation to interact with unphosporylated SP-1 and increases matrix metalloproteinase-2 (MMP-2) expression by activating the MMP-2 promoter associated with cell migration and proliferation.Conversely, knocking down hYSK1 expression activated p16 INK4a expression and suppressed MMP-2 expression. Thus, hYSK1 is necessary as a trigger for inactivating p16 INK4a and activating MMP-2 during tumor migration, suggesting that hYSK1 is a specific negative regulator of the tumor suppressor p16 INK4a and may represent a novel molecular target for reactivation of tumor suppressor genes in humans.

hYSK1 promotes cancer cell proliferation and migration through negative regulation of p16INK4a under hypoxic conditions