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

Whether the molecular drivers of tumor initiation are the same factors that promote metastasis during tumor progression is addressed in this report. In renal carcinoma, common primary driving alterations such as VHL loss do not necessarily correlate with outcome, and the authors show that additional epigenetic adaptations are required to unleash prometastatic behavior. Two important metastastic drivers, CXCR4 and CYTIP, are activated downstream of VHL loss through epigenetic reprogramming involving differential chromatin modification or DNA methylation, exemplifying the complex evolution of tumorigenic traits downstream of driving alterations. Inactivation of the von Hippel-Lindau tumor suppressor gene, VHL , is an archetypical tumor-initiating event in clear cell renal carcinoma (ccRCC) that leads 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 that is specific to metastatic ccRCC. Focusing on the two most prominent pro-metastatic VHL-HIF target genes, we show that loss of Polycomb repressive complex 2 (PRC2)-dependent histone H3 Lys27 trimethylation (H3K27me3) activates HIF-driven chemokine (C-X-C motif) receptor 4 (CXCR4) expression in support of chemotactic cell invasion, whereas loss of DNA methylation enables HIF-driven cytohesin 1 interacting protein (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.