HIF1a N-terminus hyperacetylation and the anticancer mechanism of hydroxamic HDACi Histone deacetylase inhibitors (HDACi) have shown encouraging antitumor activities. However, the mechanism mediating the antitumor effect is still unclear, which prevents the optimization of clinical designs of HDACi- based therapies and the improvement of treatment outcomes for patients with cancer. The goal of this proposal is to investigate the anticancer mechanism of hydroxamic-based HDACi involving the inhibition of hypoxia inducible factor 1 alpha (HIF1a), a protein responsible for angiogenesis and cancer development. The central hypothesis is: the inhibition of HDAC isozyme-HIF1a axis mediates the antitumor effect of hydroxamic -HDACi because specific HDAC isozymes prevent HIF1a hyperacetylation;and when these HDAC isozymes are inhibited, HIF1a is hyperacetylated at its N-terminus, which disrupts its transcriptional activity and protein stability. Therefore, identifying and targeting these specific HDAC isozymes represents a novel approach for suppressing HIF1a, angiogenesis, and tumor growth.
Three aims are proposed.
Aim 1 : We will identify the specific lysine residues that can be hyperacetylated by hydroxamic-HDACi at the HIF1a N-terminus and test the hypothesis that HIF1a N-terminal hyperacetylation disrupts HIF1a function and stability.
Aim 2 : We will identify the HDAC isozymes that must be inhibited in order to achieve HIF1a N-terminal hyperacetylation and test the hypothesis that the HIF1a N-terminal acetylation level is regulated by multiple HDAC isozymes.
Aim 3 : We will determine the biological consequences of inhibiting specific HDAC isozymes in vitro and in vivo by testing the hypothesis that disruption of HDAC isozymes - HIF1a axis can inhibit HIF1a, and impair angiogenesis and tumor growth. Our proposal will elucidate a novel mechanism by which HIF1a can be regulated by specific HDAC isozymes and will provide a mechanistic rationale for why some HDACi can inhibit HIF1a, but others cannot. This knowledge underpins the therapeutic activities of different types of HDACi in cancer and other diseases where HIF1a is etiologically and pathologically implicated and is vital for selecting the right type of HDACi for therapy.
The knowledge gained from this grant will help us to use the current cancer therapeutics more effectively and appropriately to treat cancer patients. It will also guide us to design and discover the next generation of anticancer drugs.
|Liu, Qiong; Geng, Hao; Xue, Changhui et al. (2015) Functional regulation of hypoxia inducible factor-1? by SET9 lysine methyltransferase. Biochim Biophys Acta 1853:881-91|
|Xie, Fuchun; Li, Bingbing X; Kassenbrock, Alina et al. (2015) Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. J Med Chem 58:5075-87|
|Barnett, Christine M; Heinrich, Michael C; Lim, Jeong et al. (2014) Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer. Clin Cancer Res 20:1306-12|
|Liu, Qiong; Harvey, Chris T; Geng, Hao et al. (2013) Malate dehydrogenase 2 confers docetaxel resistance via regulations of JNK signaling and oxidative metabolism. Prostate 73:1028-37|
|Geng, Hao; Liu, Qiong; Xue, Changhui et al. (2012) HIF1ýý protein stability is increased by acetylation at lysine 709. J Biol Chem 287:35496-505|
|Suwaki, Natsuko; Vanhecke, Elsa; Atkins, Katelyn M et al. (2011) A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci Transl Med 3:85ra47|
|Kachhap, Sushant; Keshamouni, Venkateshwar G; Qian, David Z et al. (2011) Cigarette smoke and cancer. J Oncol 2011:172678|
|Geng, Hao; Harvey, Chris T; Pittsenbarger, Janet et al. (2011) HDAC4 protein regulates HIF1ýý protein lysine acetylation and cancer cell response to hypoxia. J Biol Chem 286:38095-102|
|Geng, Hao; Rademacher, Brooks L; Pittsenbarger, Janet et al. (2010) ID1 enhances docetaxel cytotoxicity in prostate cancer cells through inhibition of p21. Cancer Res 70:3239-48|