Jade-1, a candidate renal tumor suppressor that promotes apoptosis.
Medical therapies are lacking for advanced renal cancer, so there is a great need to understand its pathogenesis. Most renal cancers have defects in the von Hippel-Lindau tumor suppressor pVHL. The mechanism by which pVHL protein functions in renal tumor suppression remains unclear. Jade-1 is a short-lived, kidney-enriched transcription factor that is stabilized by direct interaction with pVHL. Loss of Jade-1 stabilization by pVHL correlates with renal cancer risk, making the relationship between Jade-1 and renal cancer compelling. We report that Jade-1 expression was barely detectable in all tested renal cancer cell lines, regardless of VHL status. Strikingly, proteasome inhibitor treatment increased endogenous Jade-1 expression up to 10-fold. Jade-1 inhibited renal cancer cell growth, colony formation, and tumor formation in nude mice. Intriguingly, Jade-1 also affected the pattern of cell growth in monolayer culture and 3D culture. Jade-1 increased apoptosis by 40-50% and decreased levels of antiapoptotic Bcl-2. Antisense Jade-1-expressing cells confirmed these results. Therefore, Jade-1 may suppress renal cancer cell growth in part by increasing apoptosis. Jade-1 may represent a proapoptotic barrier to proliferation that must be overcome generally in renal cancer, perhaps initially by pVHL inactivation and subsequently by increased proteasomal activity. Therefore, Jade-1 may be a renal tumor suppressor.
Zhou
Mina I
MI
Renal and Hematology/Oncology Sections, Departments of Medicine and Pathology, Boston Medical Center, Boston University School of Medicine, Boston, MA 02118, USA.
Foy
Rebecca L
RL
Chitalia
Vipul C
VC
Zhao
Jin
J
Panchenko
Maria V
MV
Wang
Hongmei
H
Cohen
Herbert T
HT
D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D016373:DNA, Antisense / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011480:Protease Inhibitors / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein
D016373:DNA, Antisense; D018398:Homeodomain Proteins; C469360:JADE1 protein, human; D011480:Protease Inhibitors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human