Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion

Sunil Sudarshan, Karthigayan Shanmugasundaram, Susan L. Naylor, Shu Lin, Carolina B. Livi, Christine F. O'Neill, Dipen J Parekh, I. Tien Yeh, Lu Zhe Sun, Karen Block

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Article numbere21037
JournalPLoS One
Volume6
Issue number6
DOIs
StatePublished - Jun 20 2011
Externally publishedYes

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Fumarate Hydratase
kidney neoplasms
Kidney Neoplasms
Renal Cell Carcinoma
Tumors
hypoxia
kidney cells
Tricarboxylic Acids
Genes
Cells
Carcinogenesis
neoplasms
Transcription Factors
Germ-Line Mutation
carcinogenesis
cells
Tumor Suppressor Genes
Messenger RNA
tricarboxylic acids
Neoplasms

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Sudarshan, S., Shanmugasundaram, K., Naylor, S. L., Lin, S., Livi, C. B., O'Neill, C. F., ... Block, K. (2011). Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion. PLoS One, 6(6), [e21037]. https://doi.org/10.1371/journal.pone.0021037

Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion. / Sudarshan, Sunil; Shanmugasundaram, Karthigayan; Naylor, Susan L.; Lin, Shu; Livi, Carolina B.; O'Neill, Christine F.; Parekh, Dipen J; Yeh, I. Tien; Sun, Lu Zhe; Block, Karen.

In: PLoS One, Vol. 6, No. 6, e21037, 20.06.2011.

Research output: Contribution to journalArticle

Sudarshan, S, Shanmugasundaram, K, Naylor, SL, Lin, S, Livi, CB, O'Neill, CF, Parekh, DJ, Yeh, IT, Sun, LZ & Block, K 2011, 'Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion', PLoS One, vol. 6, no. 6, e21037. https://doi.org/10.1371/journal.pone.0021037
Sudarshan, Sunil ; Shanmugasundaram, Karthigayan ; Naylor, Susan L. ; Lin, Shu ; Livi, Carolina B. ; O'Neill, Christine F. ; Parekh, Dipen J ; Yeh, I. Tien ; Sun, Lu Zhe ; Block, Karen. / Reduced expression of fumarate hydratase in clear cell renal cancer mediates HIF-2α accumulation and promotes migration and invasion. In: PLoS One. 2011 ; Vol. 6, No. 6.
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