Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia

Shi,Hengliang; Zheng,Bao; Wu,Yuxuan; Tang,Yuan; Wang,Lei; Gao,Yong; Gong,Hui; Du,Jin; Yu,Rutong

doi:10.3892/or.2014.3695

Ubiquitin ligase Siah1 promotes the migration and invasion of human glioma cells by regulating HIF-1α signaling under hypoxia

Authors:
- Hengliang Shi
- Bao Zheng
- Yuxuan Wu
- Yuan Tang
- Lei Wang
- Yong Gao
- Hui Gong
- Jin Du
- Rutong Yu
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Affiliations: Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China, The Graduate School, Xuzhou Medical College, Xuzhou, Jiangsu, P.R. China
Published online on: December 23, 2014 https://doi.org/10.3892/or.2014.3695
Pages: 1185-1190

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Abstract

It has been reported that by regulating PHD3 stability, Siah1 contributes to the abundance of hypoxia-inducible factor (HIF)-1α, thereby playing an important role in the cellular response to hypoxia. However, the expression level and functional significance of Siah1 in human malignant glioma, which is characterized by high migration and invasion potential, have never been investigated. We report here, that Siah1 was expressed highly in human glioma tissues compared with its expression in normal brain tissues and was correlated with advanced tumor status and stage. The knockdown of Siah1 by short-hairpin RNA severely suppressed the migration and invasion of human glioma U251 cells under hypoxia, while overexpression of Siah1 promoted it. Furthermore, we demonstrated that the glioma cell migration and invasion under hypoxia mediated by Siah1 was achieved by reducing the stability of PHD3, which protected the HIF-1α from degradation. These findings suggest that Siah1 plays important roles in the migration and invasion of human glioma cells under hypoxia, which may provide some guidance for the targeted therapy of human glioma based on the interference of the Siah1-PHD3-HIF-1α signaling pathway.

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1	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 5:492–507. 2008. View Article : Google Scholar
2	Clarke J, Butowski N and Chang S: Recent advances in therapy for glioblastoma. Arch Neurol. 67:279–283. 2010. View Article : Google Scholar : PubMed/NCBI
3	Kaur B, Khwaja FW, Severson EA, et al: Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol. 7:134–153. 2005. View Article : Google Scholar : PubMed/NCBI
4	Vordermark D: Significance of hypoxia in malignant glioma. Re: Evans et al Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res. 11:3966–3968. 2005. View Article : Google Scholar
5	Evans SM, Judy KD, Dunphy I, et al: Hypoxia is important in the biology and aggression of human glial brain tumors. Clin Cancer Res. 10:8177–8184. 2004. View Article : Google Scholar : PubMed/NCBI
6	Kessler J, Hahnel A, Wichmann H, et al: HIF-1α inhibition by siRNA or chetomin in human malignant glioma cells: effects on hypoxic radioresistance and monitoring via CA9 expression. BMC Cancer. 10:6052010. View Article : Google Scholar
7	Wilson WR and Hay MP: Targeting hypoxia in cancer therapy. Nat Rev Cancer. 11:393–410. 2011. View Article : Google Scholar : PubMed/NCBI
8	Lipkowitz S and Weissman AM: RINGs of good and evil: RING finger ubiquitin ligases at the crossroads of tumour suppression and oncogenesis. Nat Rev Cancer. 11:629–643. 2011. View Article : Google Scholar : PubMed/NCBI
9	Jans J, van Dijk JH, van Schelven S, et al: Expression and localization of hypoxia proteins in prostate cancer: prognostic implications after radical prostatectomy. Urology. 75:786–792. 2010. View Article : Google Scholar
10	Wong CC, Zhang H, Gilkes DM, et al: Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J Mol Med. 90:803–815. 2012. View Article : Google Scholar : PubMed/NCBI
11	Dai S, Huang ML, Hsu CY and Chao KS: Inhibition of hypoxia inducible factor 1α causes oxygen-independent cytotoxicity and induces p53 independent apoptosis in glioblastoma cells. Int J Radiat Oncol Biol Phys. 55:1027–1036. 2003. View Article : Google Scholar : PubMed/NCBI
12	Lu H, Li Y, Shu M, et al: Hypoxia-inducible factor-1α blocks differentiation of malignant gliomas. FEBS J. 276:7291–7304. 2009. View Article : Google Scholar : PubMed/NCBI
13	Gillespie DL, Flynn JR, Ragel BT, et al: Silencing of HIF-1α by RNA interference in human glioma cells in vitro and in vivo. Methods Mol Biol. 487:283–301. 2009.
14	Carthew RW and Rubin GM: seven in absentia, a gene required for specification of R7 cell fate in the Drosophila eye. Cell. 63:561–577. 1990. View Article : Google Scholar : PubMed/NCBI
15	Hu G, Chung YL, Glover T, et al: Characterization of human homologs of the Drosophila seven in absentia (sina) gene. Genomics. 46:103–111. 1997. View Article : Google Scholar : PubMed/NCBI
16	Habelhah H, Frew IJ, Laine A, et al: Stress-induced decrease in TRAF2 stability is mediated by Siah2. EMBO J. 21:5756–5765. 2002. View Article : Google Scholar : PubMed/NCBI
17	Habelhah H, Laine A, Erdjument-Bromage H, et al: Regulation of 2-oxoglutarate (α-ketoglutarate) dehydrogenase stability by the RING finger ubiquitin ligase Siah. J Biol Chem. 279:53782–53788. 2004. View Article : Google Scholar : PubMed/NCBI
18	Matsuzawa SI and Reed JC: Siah-1, SIP, and Ebi collaborate in a novel pathway for β-catenin degradation linked to p53 responses. Mol Cell. 7:915–926. 2001. View Article : Google Scholar : PubMed/NCBI
19	Nakayama K, Frew IJ, Hagensen M, et al: Siah2 regulates stability of prolyl-hydroxylases, controls HIF1α abundance, and modulates physiological responses to hypoxia. Cell. 117:941–952. 2004. View Article : Google Scholar : PubMed/NCBI
20	Zhang J, Guenther MG, Carthew RW and Lazar MA: Proteasomal regulation of nuclear receptor corepressor-mediated repression. Genes Dev. 12:1775–1780. 1998. View Article : Google Scholar : PubMed/NCBI
21	Matsuo K, Satoh S, Okabe H, et al: SIAH1 inactivation correlates with tumor progression in hepatocellular carcinomas. Genes Chromosomes Cancer. 36:283–291. 2003. View Article : Google Scholar : PubMed/NCBI
22	Wen YY, Yang ZQ, Song M, et al: The expression of SIAH1 is downregulated and associated with Bim and apoptosis in human breast cancer tissues and cells. Mol Carcinog. 49:440–449. 2010.PubMed/NCBI
23	Kitagawa N, Kondo S, Wakisaka N, et al: Expression of seven-in-absentia homologue 1 and hypoxia-inducible factor 1 alpha: novel prognostic factors of nasopharyngeal carcinoma. Cancer Lett. 331:52–57. 2013. View Article : Google Scholar
24	Shi H, Gao Y, Tang Y, et al: CacyBP/SIP protein is important for the proliferation of human glioma cells. IUBMB Life. 66:286–291. 2014. View Article : Google Scholar : PubMed/NCBI
25	Liu Y, Li YM, Tian RF, et al: The expression and significance of HIF-1α and GLUT-3 in glioma. Brain Res. 1304:149–154. 2009. View Article : Google Scholar : PubMed/NCBI
26	Zhou J, Li K, Gu Y, et al: Transcriptional up-regulation of RhoE by hypoxia-inducible factor (HIF)-1 promotes epithelial to mesenchymal transition of gastric cancer cells during hypoxia. Biochem Biophys Res Commun. 415:348–354. 2011. View Article : Google Scholar : PubMed/NCBI
27	Xue Y, Li NL, Yang JY, et al: Phosphatidylinositol 3′-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1α and vascular endothelial growth factor expression. Am J Physiol Heart Circ Physiol. 300:H2169–H2176. 2011. View Article : Google Scholar : PubMed/NCBI
28	Zhang P, Zhang X, Hao X, et al: Rac1 activates HIF-1 in retinal pigment epithelium cells under hypoxia. Graefes Arch Clin Exp Ophthalmol. 247:633–639. 2009. View Article : Google Scholar : PubMed/NCBI
29	Kim JW, Gao P, Liu YC, Semenza GL and Dang CV: Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1. Mol Cell Biol. 27:7381–7393. 2007. View Article : Google Scholar : PubMed/NCBI
30	Yuan G, Nanduri J, Khan S, et al: Induction of HIF-1α expression by intermittent hypoxia: involvement of NADPH oxidase, Ca²⁺ signaling, prolyl hydroxylases, and mTOR. J Cell Physiol. 217:674–685. 2008. View Article : Google Scholar : PubMed/NCBI
31	Zhou X, Liu Z, Shi Q, et al: Geranylgeranyltransferase I regulates HIF-1α promoting glioblastoma cell migration and invasion. J Neurooncol. 112:365–374. 2013. View Article : Google Scholar : PubMed/NCBI