Abstract
The alteration of expression of p16INK4a, a well-known cyclin-dependent kinase inhibitor involved in cell cycle control, in tumors is unclear, especially under hypoxic conditions. To evaluate p16INK4a 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 p16INK4a. 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 p16INK4a under hypoxic conditions in tumors, where it negatively regulates p16INK4a, enhancing cancer cell migration. Hypoxic stimulation of hYSK1 reduces p16INK4a 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 p16INK4a expression and suppressed MMP-2 expression. Thus, hYSK1 is necessary as a trigger for inactivating p16INK4a and activating MMP-2 during tumor migration, suggesting that hYSK1 is a specific negative regulator of the tumor suppressor p16INK4a and may represent a novel molecular target for reactivation of tumor suppressor genes in humans.
Highlights
The cyclin/cyclin-dependent kinase (CDK) complexes play an important role in regulating cell cycle progression by phosphorylating specific proteins
We found that the human analog of YSK1 (hYSK1)/CDK inhibitors (CDKIs) complex increases the promoter activity of matrix metalloproteinase-2 (MMP2), thereby enhancing the invasiveness and metastatic potential of cancer cells under hypoxic conditions
To analyze the effect of hypoxia-induced hYSK1 activation on the expression of p16INK4a, we examined the effect of hYSK1 on p16INK4a expression under normoxic or hypoxic (1% O2) conditions
Summary
The cyclin/cyclin-dependent kinase (CDK) complexes play an important role in regulating cell cycle progression by phosphorylating specific proteins. During the progression of solid tumors towards malignancy, rapidly proliferating cancer cells receive an insufficient supply of growth factors, nutrients, and oxygen from the existing vasculature [14]. This results in an intratumoral hypoxic environment, which induces cell cycle arrest in some cancer cells [10]. The results of the present study revealed that hYSK1 negatively regulates p16INK4a as a representative suppressor of cell cycle progression in both the cytosol and nucleus under tumor hypoxic conditions. HYSK1 interacts with p16INK4a, thereby blocking the nuclear translocation of p16INK4a and subsequently regulates p16INK4a gene expression by activating the transcription factor specificity protein-1 (SP-1) in the nucleus during mild hypoxia. We found that the hYSK1/CDKI complex increases the promoter activity of matrix metalloproteinase-2 (MMP2), thereby enhancing the invasiveness and metastatic potential of cancer cells under hypoxic conditions
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