| RRC ID |
68748
|
| 著者 |
Vanharanta S, Shu W, Brenet F, Hakimi AA, Heguy A, Viale A, Reuter VE, Hsieh JJ, Scandura JM, Massagué J.
|
| タイトル |
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer.
|
| ジャーナル |
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.
|
| 巻・号 |
19(1)
|
| ページ |
50-6
|
| 公開日 |
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
|
| リソース情報 |
| ヒト・動物細胞 |
OS-RC-2(RCB0735) |
