title: Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion.
abstract: Germline mutations of FH, the gene that encodes for the tricarboxylic acid TCA (TCA) cycle enzyme fumarate hydratase, are associated with an inherited form of cancer referred to as Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC). Individuals with HLRCC are predisposed to the development of highly malignant and lethal renal cell carcinoma (RCC). The mechanisms of tumorigenesis proposed have largely focused on the biochemical consequences of loss of FH enzymatic activity. While loss of the tumor suppressor gene von Hippel Lindau (VHL) is thought to be an initiating event for the majority of RCCs, a role for FH in sporadic renal cancer has not been explored. Here we report that FH mRNA and protein expression are reduced in clear cell renal cancer, the most common histologic variant of kidney cancer. Moreover, we demonstrate that reduced FH leads to the accumulation of hypoxia inducible factor- 2α (HIF-2α), a transcription factor known to promote renal carcinogenesis. Finally, we demonstrate that overexpression of FH in renal cancer cells inhibits cellular migration and invasion. These data provide novel insights into the tumor suppressor functions of FH in sporadic kidney cancer.
authors.affiliation: Department of Urology, University of Texas Health Sciences Center at San Antonio, Texas, United States of America. sudarshan@uthscsa.edu
authors.forename: Sunil
authors.initials: S
authors.lastname: Sudarshan
authors.forename: Karthigayan
authors.initials: K
authors.lastname: Shanmugasundaram
authors.forename: Susan L
authors.initials: SL
authors.lastname: Naylor
authors.forename: Shu
authors.initials: S
authors.lastname: Lin
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Livi
authors.forename: Christine F
authors.initials: CF
authors.lastname: O'Neill
authors.forename: Dipen J
authors.initials: DJ
authors.lastname: Parekh
authors.forename: I-Tien
authors.initials: IT
authors.lastname: Yeh
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
authors.forename: Karen
authors.initials: K
authors.lastname: Block
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005649:Fumarate Hydratase / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005649:Fumarate Hydratase; D051057:Proto-Oncogene Proteins c-akt; D000099162:Endothelial PAS Domain-Containing Protein 1