Cancer Cell
Volume 20, Issue 4, 18 October 2011, Pages 511-523
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Article
An Antioxidant Response Phenotype Shared between Hereditary and Sporadic Type 2 Papillary Renal Cell Carcinoma

https://doi.org/10.1016/j.ccr.2011.08.024Get rights and content
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Summary

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.

Highlights

► Increased expression of AKR1B10 is a prominent feature of FH null cells ► Fumarate mediates the stabilization of NRF transcription factors ► The KEAP1-NRF axis is deregulated in type 2 papillary renal cell carcinomas ► Complete gene expression profiles of FH null kidney cancers are presented

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Present address: Center for Systems and Computational Biology, The Wistar Institute, Philadelphia, PA 19104, USA