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.