An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma.
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.
Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Aikseng
A
Ooi
Jing-Chii
JC
Wong
David
D
Petillo
Douglas
D
Roossien
Victoria
V
Perrier-Trudova
Douglas
D
Whitten
Bernice Wong Hui
BW
Min
Min-Han
MH
Tan
Zhongfa
Z
Zhang
Ximing J
XJ
Yang
Ming
M
Zhou
Betty
B
Gardie
Vincent
V
Molinié
Stéphane
S
Richard
Puay Hoon
PH
Tan
Bin Tean
BT
Teh
Kyle A
KA
Furge
D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D000975:Antioxidants / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D005649:Fumarate Hydratase / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000235:genetics / Q000502:physiology
D000975:Antioxidants; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495633:NRF1 protein, human; D051266:Nuclear Respiratory Factor 1; D012333:RNA, Messenger; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D005649:Fumarate Hydratase