Protein kinase CK2 is a key activator of histone deacetylase in hypoxia‐associated tumors
Open Access
- 16 November 2007
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 122 (2), 333-341
- https://doi.org/10.1002/ijc.23094
Abstract
Increasing evidence points to a link between histone deacetylases (HDACs) and tumorigenesis. Although several HDAC inhibitors have been tested in clinical trials for cancer therapies, the mechanisms of HDAC activation in tumors remain unknown. In this study, we investigated the pathway of HDAC activation in the context of hypoxia and inflammation, common features of solid tumors. In HeLa cells, hypoxia was a more potent activator of HDAC than IL-1β. As HDAC protein expression did not change during treatment, we hypothesized that hypoxia regulated HDAC activity through post-translational modification. We observed that hypoxia induced HDAC1 and HDAC2 protein phosphorylation both in the presence and absence of IL-1β. Using TBB, an inhibitor of protein kinase CK2, we showed that CK2 was required for hypoxia-induced HDAC activation. We also observed that CK2 activity was induced by hypoxia but not by IL-1β alone. While CK2β subunits were retained in the cytoplasm upon hypoxic treatment, CK2α and CK2α′ subunits were shuttled to the nucleus, where HDAC1 and HDAC2 are predominantly localized. Knockdown of catalytic and regulatory subunits of CK2 revealed that formation of heterotetramic complex was not required for HDAC phosphorylation. von Hippel-Lindau protein (pVHL) inactivation and hypoxia inducible factor-1α (HIF-1α) activation are associated with tumor growth and vasculogenesis. Use of Apicidin (an HDAC inhibitor) and TBB revealed that CK2-dependent HDAC activation contributed to pVHL downregulation and HIF-1α stabilization under hypoxia. Our findings that CK2 may be a key mediator for HDAC activation under hypoxia support the future application of CK2 inhibitors in cancer therapy.Keywords
Funding Information
- Japan Society for the Promotion of Science, Tokyo, Japan (15.52341, 17.05243)
- 21st Century COE program
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