The RON receptor tyrosine kinase promotes metastasis by triggering epigenetic reprogramming through the thymine glycosylase MBD4 (gene expression array)

ABSTRACT: 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 revealed that this epigenetic program is significantly associated with poor clinical outcome. Furthermore, inhibition of Ron kinase activity with a new pharmacological agent blocks metastasis of patient-derived breast tumor grafts in vivo. To determine the molecular mechanisms by which RON/MSP drives breast cancer metastasis, we performed microarray gene expression profiling of MCF7, MCF7-RON/MSP and MCF7-RON/MSP-shMBD4 cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Stephanie Cunha 

PROVIDER: E-GEOD-52567 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress