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

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Nature medicine (Impact Factor: 27.36). 12/2012; 19(1). DOI: 10.1038/nm.3029
Source: PubMed


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.

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    • "A significant aspect of VHL mutation is that it does not automatically drive ccRCC into metastasis or correlate with poor clinical outcome, but rather it is the CXCR4 expression that contributes to poor prognosis (Vanharanta et al., 2013). Recent studies demonstrate that genes beneficial for tumor cell survival and metastasis, such as CXCR4 and CYTIP, are selected for and induced through selective epigenetic changes in polycomb repression complex 2 (PRC2), eventually driving the metastatic phenotype of a subpopulation of VHL-mutated ccRCCs (Vanharanta et al., 2013). In essence, CXCR4 expression is an important prognostic factor in ccRCCs (Li et al., 2013). "
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    • "The previous studies demonstrated that CXCR4 was mediated by the hypoxia-inducible transcription factor (HIF) pathway and had a critical role in tumour initiation and metastasis in patients with RCC (Staller et al, 2003; Vanharanta et al, 2013). A recent paper reported that galectin-1 could promote tumour progression through upregulation of CXCR4 via NF-kB in RCC (Huang et al, 2014). "
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