Abstract
Abstract Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that mediates the downstream expression of genes controlling the cellular response to hypoxic conditions. Overexpression of HIF-1α has been implicated in promoting angiogenesis and a more invasive phenotype in a variety of cancer cells. HIF-1α expression may also promote chemoresistance and increased expression of the MDR gene. Previous work from our laboratory has implicated class II histone deacetylases (HDACs) as key mediators of chemoresistance, however the mechanism for this observation remains unclear. It is known that HDACs decrease HIF-1α acetylation, preventing proteosomal degradation and increasing HIF-1α activity. We hypothesized that class II HDAC modulation of HIF-1α activity may contribute to the development of resistance to anti-cancer therapy. In the present study, HDAC4 and HDAC6 expression were upregulated in doxorubicin-resistant human breast (MCF-7-DoxR), human osteosarcoma (SaOS2-DoxR) and human neuroblastoma (SK-N-SH-DoxR) cells compared to their parental cells by western blot and RT-PCR. Likewise, after treatment with deferoxamine mesylate (DFO) to prevent HIF-1α degradation under normoxic conditions, HIF-1α expression was found to be upregulated in MCF-7-DoxR and SaOS2-DoxR cells. Inhibition of HDACs with suberoylanilide hydroxamic acid (SAHA), sodium butyrate (NaB), or siRNA against HDAC4 or HDAC6 resulted in decreased HIF-1α expression and restoration of sensitivity to anti-cancer agents in both drug resistant cell lines. The percentage of viable drug-resistant cells was lower after treatment with doxorubicin plus SAHA or NaB, compared to doxorubicin, SAHA or NaB alone. In summary, HDAC regulation of HIF-1α expression may be an important mediator of tumor resistance to anti-cancer agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2549.
Published Version
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