|
| Status |
Public on Jan 02, 2014 |
| Title |
The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (RNA-Seq) |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
Metastasis is the major cause of death in cancer patients, yet the genetic/epigenetic programs that drive metastasis are poorly understood. Here, we report a novel epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by activation of the RON receptor tyrosine kinase by its ligand, macrophage stimulating protein (MSP). Through PI3K signaling, RON/MSP promotes expression of the G:T mismatch-specific thymine glycosylase MBD4. RON/MSP and MBD4-dependent aberrant DNA methylation results in misregulation of a specific set of genes. Knockdown of MBD4 reverses methylation at these specific loci, and blocks metastasis. We also show that the MBD4 glycosylase catalytic residue is required for RON/MSP-driven metastasis. Analysis of human breast cancers using a set of specific genes that are regulated by RON/MSP through MBD4-directed aberrant DNA methylation revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a new pharmacological agent prevents activation of the RON/MBD4 pathway and blocks metastasis of patient-derived breast tumor grafts in vivo.
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| |
|
| Overall design |
Examination of 3 cell types.
|
| |
|
| Contributor(s) |
Cunha S, Welm AL |
| Citation(s) |
24388747 |
| Submission date |
Nov 23, 2013 |
| Last update date |
May 15, 2019 |
| Contact name |
Stephanie Cunha |
| Organization name |
Huntsman Cancer Institute, University of Utah
|
| Department |
Oncological Science
|
| Street address |
2000 Circle of Hope
|
| City |
Salt Lake City |
| State/province |
Utah |
| ZIP/Postal code |
84116 |
| Country |
USA |
| |
|
| Platforms (1) |
| GPL9052 |
Illumina Genome Analyzer (Homo sapiens) |
|
| Samples (9)
|
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| This SubSeries is part of SuperSeries: |
| GSE52689 |
The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 |
|
| Relations |
| BioProject |
PRJNA229803 |
| SRA |
SRP033282 |
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