In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1512-1512
Abstract:
Blood coagulation factor VII (fVII) is a key enzyme of the extrinsic coagulation cascade that is produced predominantly by hepatocytes. Tissue factor/fVIIa complex formation on the cell surface initiates key pathogenic mechanisms in cancer, including cell motility, invasion, cell survival, and angiogenesis. We have shown that various cancer cells ectopically synthesize fVII, resulting in activation of cell motility and invasion [1]. We have also shown that fVII expression is ectopically induced in ovarian cancer cells under hypoxia, potentially leading to a major complication of cancer patients, thromboembolism via secretion of fVII-positive microparticles [2] . Hypoxia inducible factors HIF1α and HIF2α are known to form a heterodimeric complex with a constitutively expressed aryl hydrocarbon receptor nuclear translocator (ARNT). HIF-ARNT complex binds to hypoxia response elements (HREs) within gene regulatory regions, resulting in transcriptional activation. We previously found that fVII gene (FVII) is inducible under hypoxia by HIF2α dependent mechanism. Unexpectedly, chromatin immunoprecipitation (ChIP) analysis revealed that HIF2α but not HIF1α was found to bind to FVII promoter without HRE [1]. In this study, we further investigated this characteristic transcriptional activation mechanism. Reporter gene, ChIP, and RNA interference (RNAi) experiments revealed that interaction between Sp1 and HIF2α in the promoter region is essential for FVII induction. Histone acetylation is known as a major mechanism for transcriptional activation. Thus, we additionally investigated effect of histone acetylation within the promoter region on HIF2α-Sp1 mediated transcriptional activation. We unexpectedly found that unlike typical transcriptional activation mechanisms, acetylation of histones negatively regulates FVII gene induction. ChIP and RNAi, followed by real-time PCR analysis revealed that a class II histone deacetylase HDAC4 is recruited to FVII promoter under hypoxia and is a coactivator responsible for this transcriptional induction. Furthermore, immunohistochemical experiments with an ovarian cancer xenograft model revealed that fVII presents in tissues strongly expressing HIF2α. These results suggest that hypoxic activation of FVII gene in cancer cells involves novel deacetylation dependent mechanism mediated by HIF2α-Sp1 interaction. References [1] Koizume, S. et al. Cancer Res. 66: 9453-9460, 2006. [2] Yokota, N. et al. Br. J. Cancer, 10 1: 2023-2029, 2009. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1512. doi:10.1158/1538-7445.AM2011-1512
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2011-1512
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2011
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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