Epigenetic silencing of Na,K-ATPase β 1 subunit gene ATP1B1 by methylation in clear cell renal cell carcinoma.
The Na,K-ATPase or sodium pump carries out the coupled extrusion of Na(+) and uptake of K(+) across the plasma membranes of cells of most higher eukaryotes. We have shown earlier that Na,K-ATPase-β 1 (NaK-β) protein levels are highly reduced in poorly differentiated kidney carcinoma cells in culture and in patients' tumor samples. The mechanism(s) regulating the expression of NaK-β in tumor tissues has yet to be explored. We hypothesized that DNA methylation plays a role in silencing the NaK-β gene (ATP1B1) expression in kidney cancers. In this study, to the best of our knowledge we provide the first evidence that ATP1B1 is epigenetically silenced by promoter methylation in both renal cell carcinoma (RCC) patients' tissues and cell lines. We also show that knockdown of the von Hippel-Lindau (VHL) tumor suppressor gene in RCC cell lines results in enhanced ATP1B1 promoter AT hypermethylation, which is accompanied by reduced expression of NaK-β. Furthermore, treatment with 5-Aza-2'-deoxycytidine rescued the expression of ATP1B1 mRNA as well as NaK-β protein in these cells. These data demonstrate that promoter hypermethylation is associated with reduced NaK-β expression, which might contribute to RCC initiation and/or disease progression.
Nemours Center for Childhood Cancer Research; Alfred I. duPont Hospital for Children; Wilmington, DE USA.
Ponniah
P
Selvakumar
Nemours Center for Childhood Cancer Research; Alfred I. duPont Hospital for Children; Wilmington, DE USA.
Tori A
TA
Owens
Nemours Center for Childhood Cancer Research; Alfred I. duPont Hospital for Children; Wilmington, DE USA; Department of Biological Sciences; University of Delaware; Newark, DE USA.
Justin M
JM
David
Helen F. Graham Center; Christiana Care Health System; Newark, DE USA.
Nicholas J
NJ
Petrelli
Department of Community and Family Medicine; Section of Biostatistics and Epidemiology; The Geisel School of Medicine at Dartmouth; Hanover, NH USA; Department of Pharmacology and Toxicology; The Geisel School of Medicine at Dartmouth; Hanover, NH USA.
Brock C
BC
Christensen
Department of Pharmaceutical Sciences; School of Pharmacy; Thomas Jefferson University; Philadelphia, PA USA.
Ashakumary
A
Lakshmikuttyamma
Nemours Center for Childhood Cancer Research; Alfred I. duPont Hospital for Children; Wilmington, DE USA.
Ayyappan K
AK
Rajasekaran
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D044127:Epigenesis, Genetic; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
C503551:ATP1B1 protein, human; C000717967:DNMT3A protein, human; D012333:RNA, Messenger; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000254:Sodium-Potassium-Exchanging ATPase; D001374:Azacitidine
ATP1B1; DNA methylation; Na,K-ATPase; epigenetics; renal cell carcinoma