hYSK1 promotes cancer cell proliferation and migration through negative regulation of p16INK4a under hypoxic conditions
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Mee-Hyun Lee1, Zigang Dong1,6, Young-Joon Surh2,3,4,5 and Bu Young Choi7
1China-US (Henan) Hormel Cancer Institute, Zhengzhou 450008, China
2Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
3Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, South Korea
4Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Sciences and Technology, Seoul National University, Seoul 08826, South Korea
5Cancer Research Institute, Seoul National University, Seoul 110-744, South Korea
6The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
7Department of Pharmaceutical Science & Engineering, Seowon University, Cheongju 28674, South Korea
Bu Young Choi, email: firstname.lastname@example.org
Keywords: hYSK1, p16INK4a, MMP-2, tumor migration, hypoxia
Received: July 17, 2017 Accepted: August 27, 2017 Published: October 06, 2017
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.
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