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Cancer Cell. 2011 Oct 18;20(4):511-23. doi: 10.1016/j.ccr.2011.08.024.

An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma.

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Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.


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.

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