Abstract
Despite recent advances in cancer therapies, metastatic renal cell carcinoma (RCC) remains difficult to treat. Most RCCs result from inactivation of the von Hippel Lindau (VHL) tumor suppressor, leading to stable expression of Hypoxia-Inducible Factor-alpha (HIF-1alpha, -2alpha, -3alpha) and the induction of downstream target genes, including those responsible for angiogenesis and metastasis. While VHL is inactivated in the majority of RCC cases, expression of the PTEN tumor suppressor is reduced in about 30% of cases. PTEN functions to antagonize PI3K/Akt/mTOR signaling, thereby controlling cell growth and survival. Activation of PI3K/Akt/mTOR leads to increased HIF-1alpha expression in certain cancer cells, supporting the rationale of using mTOR inhibitors as anti-cancer agents. Notably, HIF-2alpha, rather than HIF-1alpha, has been shown to play a critical role in renal tumorigenesis. To investigate whether HIF-2alpha is similarly regulated by the PI3K pathway in VHL(-/-)RCC cells, we manipulated PI3K signaling using PTEN overexpression and siRNA knockdown studies and pharmacologic inhibition of PI3K or Akt. Our data support a novel role for wild-type PTEN in promoting HIF-2alpha activity in VHL null RCC cells. This mechanism is unique to the cellular environment in which HIF-2alpha expression is deregulated, resulting from the loss of VHL function. Our data show that PTEN induces HIF-2alpha transcriptional activity by inhibiting expression of Yin Yang 1 (YY1), which acts as a novel corepressor of HIF-2alpha. Further, PTEN suppression of YY1 is mediated through antagonism of PI3K signaling. We conclude that wild-type PTEN relieves the repressive nature of YY1 at certain HIF-2alpha target promoters and that this mechanism may promote early renal tumorigenesis resulting from VHL inactivation by increasing HIF-2alpha activity.