|
| Status |
Public on Dec 05, 2012 |
| Title |
Epigenetic expansion of VHL-HIF signal output drives multiorgan metastasis in renal cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
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.
This SuperSeries is composed of the SubSeries listed below.
|
| |
|
| Overall design |
Refer to individual Series.
|
| |
|
| Contributor(s) |
Vanharanta S, Massague J |
| Citation(s) |
23223005 |
| |
| Submission date |
Sep 22, 2011 |
| Last update date |
Mar 06, 2013 |
| Contact name |
Sakari Vanharanta |
| E-mail(s) |
[email protected]
|
| Organization name |
University of Helsinki
|
| Department |
Translational Cancer Medicine Program
|
| Lab |
Vanharanta
|
| Street address |
Haartmaninkatu 8
|
| City |
Helsinki |
| ZIP/Postal code |
00014 |
| Country |
Finland |
| |
|
| Platforms (2) |
| GPL6791 |
Affymetrix GeneChip Human Genome U133 Plus 2.0 Array [CDF: Hs_ENTREZG_10] |
| GPL14604 |
Affymetrix GeneChip Human Genome U133A 2.0 Array [CDF: Brainarray Version 10, Hs133Av2_Hs_ENTREZG] |
|
| Samples (26)
|
|
| This SuperSeries is composed of the following SubSeries:
|
| GSE32295 |
Gene expression data from the 786-O renal cell carcinoma cell line and its metastatic derivatives. |
| GSE32297 |
Gene expression changes in response to VHL-reintroduction in metastatic 786-M1A cells. |
| GSE32298 |
Gene expression changes in 786-O cells in response to 5DC treatment. |
| GSE35417 |
Gene expression changes in 786-O cells in response to SUZ12 knockdown. |
|
| Relations |
| BioProject |
PRJNA146371 |
Less...
More...