Epigenetic expansion of VHL-HIF signal output drives multi-organ metastasis in renal cancer

Inactivation of the von Hippel-Lindau tumor suppressor (VHL) is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC), leading to the activation of hypoxia-inducible transcription factors (HIFs). However, VHL mutation status in ccRCC is not correlated with clinical outcome. Here we show that during ccRCC progression, cancer cells exploit diverse epigenetic alterations to empower a branch of the VHL-HIF pathway for metastasis, and the strength of this activation is associated with poor clinical outcome. By analyzing metastatic subpopulations of VHL-deficient ccRCC cells, we discovered an epigenetically altered VHL-HIF response specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that liberation from PRC2-dependent repressive histone methylation (H3K27me3) activates HIF-driven CXCR4 expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven CYTIP expression to protect cancer cells from death cytokine signals. Thus, metastasis in ccRCC is based on an epigenetically expanded output of the tumor-initiating pathway.