Independence of HIF1a and androgen signaling pathways in prostate cancer

Androgen signaling drives prostate cancer progression and is a therapeutic target. Hypoxia/HIF1a signaling is associated with resistance to hormone therapy and a poor prognosis in patients treated with surgery or radiotherapy. It is not known whether the pathways operate in cooperation or independently. Using LNCaP cells with and without stable transfection of a HIF1a expression vector, we show that combined AR and HIF1a signaling promotes tumor growth in vitro and in vivo, and the capacity of HIF1a to promote tumor growth in the absence of endogenous androgen in vivo. Gene expression analysis identified 7 genes that were upregulated by both androgen and HIF1a. ChIP-Seq analysis showed that the AR and HIF/hypoxia signaling pathways function independently regulating the transcription of different genes with few shared targets. In clinical datasets elevated expression of 5 of the 7 genes was associated with a poor prognosis. Our findings suggest that simultaneous therapeutic inhibition of AR and HIF1a signaling pathways should be explored as a potential therapeutic strategy.