HIF2ɑ Requires Engagement with YAP/TAZ and AP-1 Transcription Factors to Maintain Oncogenic Transcription in Clear Cell Renal Cell Carcinoma [CUT&Tag]

Clear Cell Renal Cell Carcinoma (ccRCC) is characterized by loss of tumor suppressor von Hippel-Lindau (VHL), leading to activation of Hypoxia-inducible Factor 2ɑ (HIF2ɑ) oncogenic transcription factor and pseudo-hypoxia. Integrated analysis of public ccRCC multi-omic datasets revealed frequent inactivation of the Hippo tumor suppressor pathway and corresponding increase in YAP/TAZ transcription activity in ccRCC tumors, which is associated with worse overall survival in treatment naïve patients. By combining Cut&Tag and BRB-seq analysis, we assessed the chromatin binding and gene regulation of YAP and HIF2ɑ, and unveiled that these two proteins are co-recruited to AP-1 sites through interactions with the AP-1 transcription factors. YAP/TAZ, HIF2ɑ and JUN are dependent on each other to maintain their expression, and function cooperatively to promote the expression of highly expressed transcription factors and other important oncogenes. Our findings not only revealed the therapeutic potentials of adjunct YAP/TAZ-based therapies in the treatment of advanced ccRCC, but also revealed novel mechanistic insights into the dynamic interactions among YAP, HIF2ɑ and AP-1 proteins that could be further exploited to improve treatment for ccRCC.