Reference - Detail
| RRC ID | 68748 |
|---|---|
| Author | Vanharanta S, Shu W, Brenet F, Hakimi AA, Heguy A, Viale A, Reuter VE, Hsieh JJ, Scandura JM, Massagué J. |
| Title | Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer. |
| Journal | Nat Med |
| Abstract |
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. |
| Volume | 19(1) |
| Pages | 50-6 |
| Published | 2013-1-1 |
| DOI | 10.1038/nm.3029 |
| PII | nm.3029 |
| PMID | 23223005 |
| PMC | PMC3540187 |
| MeSH | Animals Base Sequence Carcinoma, Renal Cell / genetics Carcinoma, Renal Cell / metabolism* Carcinoma, Renal Cell / pathology Carcinoma, Renal Cell / secondary* Cell Line, Tumor DNA Methylation Gene Expression Regulation, Neoplastic Histones / metabolism Humans Hypoxia-Inducible Factor 1 / metabolism* Kidney Neoplasms / genetics Kidney Neoplasms / metabolism* Kidney Neoplasms / pathology* Mice Mice, Inbred NOD Mice, SCID Neoplasm Metastasis Polycomb Repressive Complex 2 / genetics Receptors, CXCR4 / genetics Receptors, CXCR4 / metabolism* Sequence Analysis, DNA Transcription Factors / genetics Transcription Factors / metabolism* Von Hippel-Lindau Tumor Suppressor Protein / metabolism* |
| IF | 36.13 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 69 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | OS-RC-2(RCB0735) |