Circadian regulation of HIF2alpha in ccRCC

PROJECT SUMMARY (DESCRIPTION) Clear cell renal cell carcinoma (ccRCC) is frequently driven by increased activity of the hypoxia-inducible transcription factor HIF2. Circadian rhythms coordinate behavior and physiology with predictable daily environmental cycles. Chronic disruption of circadian rhythms, such as that experienced during shift work or travel across time zones, increases the risk of several types of cancer in people. We have established that the circadian clock components BMAL1, CRY1, and CRY2 regulate the activity of HIF2. In Aim 1 of this project, we will determine the molecular mechanisms by which BMAL1, BMAL2, CRY1, and CRY2 influence HIF2-dependent gene expression in ccRCC cells. In Aim 2 of this project, we will investigate the impact of depletion of CRY1, CRY2, or BMAL1 on the growth of ccRCC cell lines and xenograft tumors.