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Molecular and Cellular Biology, August 2009, p. 4080-4090, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00483-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Fumarate Hydratase Deficiency in Renal Cancer Induces Glycolytic Addiction and Hypoxia-Inducible Transcription Factor 1{alpha} Stabilization by Glucose-Dependent Generation of Reactive Oxygen Species{triangledown}

Sunil Sudarshan,1,2 Carole Sourbier,1 Hye-Sik Kong,1 Karen Block,3 Vladimir A. Valera Romero,1 Youfeng Yang,1 Cynthia Galindo,2 Mehdi Mollapour,1 Bradley Scroggins,1 Norman Goode,1 Min-Jung Lee,4 Campbell W. Gourlay,5 Jane Trepel,4 W. Marston Linehan,1 and Len Neckers1*

Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892,1 Departments of Urology,2 Nephrology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78212,3 Medical Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892,4 Department of Biosciences, University of Kent, Canterbury, Kent CT2 7NJ, United Kingdom5

Received 14 April 2009/ Accepted 15 May 2009

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an inherited cancer syndrome linked to biallelic inactivation of the gene encoding the tricarboxylic acid cycle enzyme fumarate hydratase (FH). Individuals with HLRCC are at risk to develop cutaneous and uterine leiomyomas and an aggressive form of kidney cancer. Pseudohypoxic drive—the aberrant activation of cellular hypoxia response pathways despite normal oxygen tension—is considered to be a likely mechanism underlying the etiology of this tumor. Pseudohypoxia requires the oxygen-independent stabilization of the {alpha} subunit of the hypoxia-inducible transcription factor (HIF-1{alpha}). Under normoxic conditions, proline hydroxylation of HIF-1{alpha} permits VHL recognition and subsequent targeting for proteasomal degradation. Here, we demonstrate that inactivating mutations of FH in an HLRCC-derived cell line result in glucose-mediated generation of cellular reactive oxygen species (ROS) and ROS-dependent HIF-1{alpha} stabilization. Additionally, we demonstrate that stable knockdown of FH in immortalized renal epithelial cells results in ROS-dependent HIF-1{alpha} stabilization. These data reveal that the obligate glycolytic switch present in HLRCC is critical to HIF stabilization via ROS generation.

* Corresponding author. Mailing address: Urologic Oncology Branch, National Cancer Institute, NIH, Bethesda, MD 20892. Phone: (301) 496-5899. Fax: (301) 402-0922. E-mail: neckersl{at}mail.nih.gov

{triangledown} Published ahead of print on 26 May 2009.

Molecular and Cellular Biology, August 2009, p. 4080-4090, Vol. 29, No. 15
0270-7306/09/$08.00+0     doi:10.1128/MCB.00483-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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