Inhibition of Mxi1 suppresses HIF-2α-dependent renal cancer tumorigenesis

In clear cell renal cancers, the primary molecular defect is inactivation of the von Hippel-Lindau (VHL) gene. Loss of pVHL, the VHL gene product, leads to constitutive activation of hypoxia-inducible factor (HIF) signaling. While downregulation of HIF suppresses tumor formation by pVHL-defective re...

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Bibliographic Details
Published in:Cancer biology & therapy 2008-10, Vol.7 (10), p.1619-1627
Main Authors: Tsao, Chun Chui, Teh, Bin T., Jonasch, Eric, Shreiber-Agus, Nicole, Efstathiou, Eleni, Hoang, Anh, Czerniak, P. Bogdan, Logothetis, Christopher, Corn, Paul G.
Format: Article
Language:English
Subjects:
Binding
Biology
Bioscience
Calcium
Cancer
Cell
Cycle
Landes
Organogenesis
Proteins
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Summary:In clear cell renal cancers, the primary molecular defect is inactivation of the von Hippel-Lindau (VHL) gene. Loss of pVHL, the VHL gene product, leads to constitutive activation of hypoxia-inducible factor (HIF) signaling. While downregulation of HIF suppresses tumor formation by pVHL-defective renal carcinoma cells, the relative contribution of individual HIF regulated genes to HIF-dependent tumorigenesis remains under investigation. Mxi1, a c-Myc antagonist, is a HIF target gene that inhibits mitochondrial biogenesis, reprograms cellular energy metabolism, and protects cells from c-Myc-dependent apoptosis in vitro. In the present study we show that Mxi1 is overexpressed in primary human clear cell kidney cancers. Inhibition of Mxi1 in pVHL-defective kidney cancer cells using shRNA alters their cell-cycle parameters, inhibits their ability to invade matrigel, and suppresses their ability to form tumors in vivo. Compared to Mxi1-proficient tumors, Mxi1-deficient tumors display reduced cellular proliferation. These results establish Mxi1 as an important downstream target of HIF that contributes to pVHL-deficient renal cancer tumorigenesis.
ISSN:1538-4047
1555-8576
DOI:10.4161/cbt.7.10.6583