Androgen deprivation therapy-induced epithelial-mesenchymal transition of prostate cancer through downregulating SPDEF and activating CCL2

Abstract

The chemokine CC 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.

Genetics in the Prostate Cancer

“…Interestingly, inactivation of the androgen receptor resulted in lower expression of a transcriptional repressor (SAM pointed domain-containing ETS transcription factor, SPDEF) of CCL2, which mediates epithelial to mesenchymal cell transition of the prostate cancer cells. That may explain progression to metastatic stage in a subset of castration resistant prostate cancer [70].…”

Transcriptional mediators of treatment resistance in lethal prostate cancer

“…Among the transcriptional regulators with decreased activity in small cell carcinoma are HOXB13 , which mediates AR regulatory activity and response to androgens, and BHLHE40 , previously reported to be regulated by AR 25–27 . Several ETS family transcription factors showed reduced activity in small cell carcinoma, including ETV1 , which increases prostate adenocarcinoma invasiveness, EHF , whose loss confers stem-like features, and SPDEF , an AR-regulated transcription factor whose downregulation promotes EMT 28–30 . On the other hand, considering transcriptional regulators with increased regulon expression in small cell carcinoma, we noted the stemness-promoting factors NANOG and SOX2 and the epigenetic regulator EZH2 , all of which have been reported to promote lineage plasticity and resistance to androgen-targeting therapies 23,31–33 .…”

ELF3, ELF5, EHF and SPDEF Transcription Factors in Tissue Homeostasis and Cancer

“…SPDEF is also regulated by AR signalling in prostate cancer, which has both beneficial and potentially detrimental effects when AR signaling is inhibited by androgen deprivation therapy (ADT). Specifically, AR-mediated activation of SPDEF repressed expression of TGFBI and CCL2 , key drivers of prostate cancer metastasis [ 104 , 105 ]. ADT relieves this repression and inadvertently promotes metastasis by increasing TGFBI and CCL2 expression, providing an example of how a therapy which blocks growth of the primary tumour may paradoxically promote metastasis.…”