The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming
Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by th...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2014-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713007559 |
| _version_ | 1819152650801774592 |
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| author | Stéphanie Cunha Yi-Chun Lin Elizabeth A. Goossen Christa I. DeVette Mark R. Albertella Stuart Thomson Mark J. Mulvihill Alana L. Welm |
| author_facet | Stéphanie Cunha Yi-Chun Lin Elizabeth A. Goossen Christa I. DeVette Mark R. Albertella Stuart Thomson Mark J. Mulvihill Alana L. Welm |
| author_sort | Stéphanie Cunha |
| collection | DOAJ |
| description | Metastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the 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 the 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 revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo. |
| first_indexed | 2024-12-22T14:52:40Z |
| format | Article |
| id | doaj.art-c5c460c2ffbb46b78a441db65573d121 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T14:52:40Z |
| publishDate | 2014-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-c5c460c2ffbb46b78a441db65573d1212022-12-21T18:22:17ZengElsevierCell Reports2211-12472014-01-016114115410.1016/j.celrep.2013.12.010The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation ReprogrammingStéphanie Cunha0Yi-Chun Lin1Elizabeth A. Goossen2Christa I. DeVette3Mark R. Albertella4Stuart Thomson5Mark J. Mulvihill6Alana L. Welm7Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USAOSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USAOSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USAOSI/Astellas, Bioscience Park Drive, Farmingdale, NY 11735, USADepartment of Oncological Sciences, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT 84112, USAMetastasis is the major cause of death in cancer patients, yet the genetic and epigenetic programs that drive metastasis are poorly understood. Here, we report an epigenetic reprogramming pathway that is required for breast cancer metastasis. Concerted differential DNA methylation is initiated by the 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 the 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 revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo.http://www.sciencedirect.com/science/article/pii/S2211124713007559 |
| spellingShingle | Stéphanie Cunha Yi-Chun Lin Elizabeth A. Goossen Christa I. DeVette Mark R. Albertella Stuart Thomson Mark J. Mulvihill Alana L. Welm The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming Cell Reports |
| title | The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming |
| title_full | The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming |
| title_fullStr | The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming |
| title_full_unstemmed | The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming |
| title_short | The RON Receptor Tyrosine Kinase Promotes Metastasis by Triggering MBD4-Dependent DNA Methylation Reprogramming |
| title_sort | ron receptor tyrosine kinase promotes metastasis by triggering mbd4 dependent dna methylation reprogramming |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713007559 |
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