Open AccessReduced Expression of Fumarate Hydratase in Clear Cell Renal Cancer Mediates HIF-2α Accumulation and Promotes Migration and Invasion
Author(s) -
Sunil Sudarshan,
Karthigayan Shanmugasundaram,
Susan L. Naylor,
Shu Chun Lin,
Carolina B. Livi,
Christine F. O’Neill,
Dipen J. Parekh,
ITien Yeh,
LuZhe Sun,
Karen Block
Publication year - 2011
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0021037
Subject(s) - fumarase , carcinogenesis , cancer research , biology , cancer , kidney cancer , clear cell renal cell carcinoma , cancer cell , transcription factor , tumor suppressor gene , renal cell carcinoma , kidney , pathology , medicine , endocrinology , gene , genetics
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.