Inhibition of Mxi1 suppresses HIF-2alpha-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 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.
Tsao
Chun Chui
CC
Department of Genitourinary Medical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
Teh
Bin T
BT
Jonasch
Eric
E
Shreiber-Agus
Nicole
N
Efstathiou
Eleni
E
Hoang
Anh
A
Czerniak
Bogdan
B
Logothetis
Christopher
C
Corn
Paul G
PG
D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D049109:Cell Proliferation; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D007680:Kidney Neoplasms / Q000378:metabolism*; D007797:Laminin / Q000737:chemistry; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D011509:Proteoglycans / Q000737:chemistry; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D003094:Collagen; D004338:Drug Combinations; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007797:Laminin; D011509:Proteoglycans; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497442:HIF1A protein, human; C079440:MXI1 protein, human; C059485:matrigel; C497446:VHL protein, human