The chemokine C–C motif ligand 2 (CCL2) is important in recruiting tumor-associated macrophages and is involved in the development of castration-resistance prostate cancer (CRPC) after androgen-deprivation therapy (ADT); however, the underlying mechanism remains unclear. We found that inactivation of the androgen receptor (AR) reduces a transcriptional repressor (SAM pointed domain-containing ETS transcription factor, SPDEF) of CCL2, which mediates epithelial-to-mesenchymal transition (EMT) of prostate tumor cells. Cell lines derived from a prostate-specific Pten/Trp53-null mouse and capable of a spontaneous EMT were utilized for identification of CCL2, and showed that reduced SPDEF expression was associated with an elevated CCL2-activated EMT. AR signaling inhibits CCL2 through a SPDEF-mediated mechanism in that the SPDEF recognizes the CCL2 promoter and transcriptionally represses its activity. Ectopically expressed SPDEF reduced the EMT and rescued expression of CCL2 in SPDEF-expressing cells, which induced the EMT and promotes malignant functions of prostate cancer cells. In tissues from prostate cancer patients with ADT, low SPDEF levels were correlated with high CCL2 expression compared to patients without ADT. We present a novel mechanism that contributes to the EMT and metastatic phenotype observed in a subset of ADT-resistant prostate cancer, where the CCL2 is stimulated through the inactivated of AR-mediated SPDEF.
|Number of pages||11|
|Journal||Biochimica et Biophysica Acta - Molecular Basis of Disease|
|Publication status||Published - May 1 2018|
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology