Abstract
Fumarate hydratase (FH) mutation causes hereditary type 2 papillary renal cell carcinoma (PRCC2). The main effect of FH mutation is fumarate accumulation. The current paradigm posits that the main consequence of fumarate accumulation is HIF-α stabilization. Paradoxically, FH mutation differs from other HIF-α stabilizing mutations, such as VHL and SDH mutations, in its associated tumor types. We identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes. We demonstrated that aldo-keto reductase family 1 member B10 (AKR1B10) is an ARE-controlled gene and is up-regulated upon FH knockdown as well as in FH null cell lines. AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2. This phenotype better explains the similarities between hereditary and sporadic PRCC2.
Original language | English (US) |
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Pages (from-to) | 511-523 |
Number of pages | 13 |
Journal | Cancer cell |
Volume | 20 |
Issue number | 4 |
DOIs | |
State | Published - Oct 18 2011 |
Funding
We thank Sabrina Noyes for administrative support and David Nadziejka for technical editing. We acknowledge the Van Andel Research Foundation, the Singapore Millennium Foundation, and Fondation IGR & INCa (PNES Rein and Centre Expert National Cancers Rares PREDIR) for funding. A.O., K.F., and B.T. designed the study; A.O. performed all experiments, bioinformatics, and data analysis; J.C.W. and D.R. performed IHC staining; D.P. performed microarray experiments; D.W. performed tandem mass spectrometry; and X.J.Y. and M.Z. performed histological evaluation. B.T., Z.Z., M.Z., M.H.T., B.H.W., V.P.T., P.H.T., B.G., V.M., and S.R. provided samples and clinical data. A.O. and K.F. prepared the manuscript. Mass spectrometry and data analysis were performed in the Michigan State University, Proteomic Core Facility.
ASJC Scopus subject areas
- Oncology
- Cancer Research