Hypoxia inducible factors (HIF-1 and HIF-2) are potential therapeutic targets for both cancer and ischemic disorders, particularly for hypoxic and angiogenic tumors that are usually resistant to traditional radiation and chemotherapy. Blocking tumor angiogenesis has been extensively explored as a novel treatment for cancers for the past decade. The identification of HIF function as a master regulator of multiple angiogenic signaling pathways and the complete dissection of the conventional regulatory mechanisms of HIF function provide the possibility to target HIF as a better alternative to current anti-angiogenesis therapies. The fact that HIF function also promotes cell proliferation and survival by non-angiogenic mechanisms adds additional benefits to therapies based-on modulating HIF. Interestingly, in addition to HIF inhibitors identified by compound screening processes, basic research and clinical trials have shown that several classes of structurally distinct new anti-cancer, small molecular weight compounds, including histone deacetylase inhibitors, heat shock protein 90 inhibitors, proteasomal inhibitors and compounds disturbing microtubule dynamics, block angiogenesis and suppress tumor growth, at least in part, through repressing HIF function. Since these compounds were not originally designed to target HIF, the unexpected convergence suggests that a coordinated process involving multiple basic cellular systems controls HIF function. We found that HDACI- mediated protein acetylation events might modify the function and interactions of the heat shock protein machinery with HIF-1a and an acetylated p60 protein. In addition, we have found that HDACIs stimulate the expression of HDAC3 and Sirt2, two potential repressors of HIF-1 activity. Our central hypotheses to be tested are: 1) an orchestrated quality control system (QCS) plays a central role in regulating HIF-1a stability, and this QCS involves Hsp70/Hsp90, vimentin, proteasome and microtubule function;and 2) histone deacetylase inhibitor-induced repression of HIF-1 transactivation potential involves one or more negative regulators. We will use HIF-1 as a model: 1) to investigate the roles of Hsp90, the acetyl p60 and their acetylation in the HIF- 11 QCS;2) to investigate the molecular basis underlying the degradation-independent repression of HIF-1, 21 transactivation potential by HDACIs;and 3) to examine the relevance of identified deacetylases and substrates to tumorigenesis and angiogenesis in human endothelial culture, tumor cell culture, and in mouse xenograft/orthotopic tumor models. Results from this study will contribute to the development and improvement of new therapies for a variety of tumors and ischemic disorders. PULBIC
This project studies the quality control and functional regulation of two important transcription factors (HIF-1, 2) that govern the supply of oxygen and nutrients to tumors and normal body parts, aiming to gain new knowledge that may eventually facilitate the development of novel, safe and efficient therapies for various tumors and disorders caused by insufficient blood supply, such as heart diseases and stroke.
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