Elevation of androgen receptor promotes prostate cancer metastasis by induction of epithelial‐mesenchymal transition and reduction of KAT5

Abstract

Androgen receptor (AR), an androgen‐activated transcription factor, belongs to the nuclear receptor superfamily. AR plays an important role in the development and progression of prostate cancer (PCa). However, the role of AR in PCa metastasis is not fully understood. To investigate the role of AR in PCa metastasis, we examined AR expression level in primary and metastatic PCa by analyzing gene array data of 378 primary prostate tumors and 120 metastatic prostate tumors from Oncomine, as well as carrying out immunohistochemical (IHC) staining of 56 prostate cancer samples. Expression of mRNA and protein of AR as well as its target gene prostate‐specific antigen (PSA) was much higher in metastatic prostate tumors than in primary prostate tumors. Knockdown of AR with siRNA or treating with anti‐androgen Casodex reduced migration and invasion ability of C4‐2B PCa cells. Knockdown of AR increased protein expression of E‐cadherin and AR coregulator KAT5 but reduced expression of epithelial‐mesenchymal transition (EMT) marker proteins Slug, Snail, MMP‐2, vimentin, and β‐catenin. Knockdown of KAT5 increased migration of C4‐2B cells, whereas overexpression of KAT5 suppressed cell migration. KAT5 knockdown rescues the suppressive effect of AR knockdown on migration of C4‐2B cells. Gene expression level of AR and KAT5 showed a negative correlation. PCa patients with higher AR expression or lower KAT5 expression correlated with shorter recurrence‐free survival. Our study suggested that elevation of AR expression and AR signaling in prostate tumors promotes PCa metastasis by induction of EMT and reduction of KAT5.

ARe we there yet? Understanding androgen receptor signaling in breast cancer

“…The AR pathway and AR splice variants have been implicated in metastatic phenotypes in prostate cancer 122 . Gene array and IHC data of both primary and metastatic tumors demonstrate that AR mRNA and protein expression are significantly higher in metastases compared to primary prostate lesions 123 . In vitro, increased AR expression in prostate tumors also led to the formation of metastases and induction of the epithelial to mesenchymal transition (EMT) 123 , the process by which cells lose their polarity and gain the ability to migrate and become invasive.…”

“…Gene array and IHC data of both primary and metastatic tumors demonstrate that AR mRNA and protein expression are significantly higher in metastases compared to primary prostate lesions 123 . In vitro, increased AR expression in prostate tumors also led to the formation of metastases and induction of the epithelial to mesenchymal transition (EMT) 123 , the process by which cells lose their polarity and gain the ability to migrate and become invasive. In addition, during prostate cancer development, the presence of fibroblasts provides important structural and functional changes that regulate the extracellular matrix 124 .…”

The Prospect of Identifying Resistance Mechanisms for Castrate-Resistant Prostate Cancer Using Circulating Tumor Cells: Is Epithelial-to-Mesenchymal Transition a Key Player?

“…Further, knockdown of AR using siRNA in C4-2B cells suppressed functional markers of EMT, viz cell migration and invasion, and mesenchymal marker proteins associated with EMT, while increasing the epithelial marker E-cadherin. ese effects were recapitulated by treatment with the antiandrogen bicalutamide [39]. us, it appears that AR stimulation induces or suppresses EMT in cell culture in a cell-type-dependent fashion.…”

“…When its ligand, dihydrotestosterone (DHT) or testosterone, binds via the AR ligand-binding domain (LBD) (Figure 2(a)), a structural change results in the detachment of AR from the heat-shock protein 90 (HSP90) complex, homodimerization of the receptor, and nuclear translocation. [39]; other data suggest AR reverses EMT and ADT can induce EMT [40,41] Cell proliferation and tumor progression [42,43] Different AR expression patterns, amplification, mutation, and variant expression in PCa CTC [44][45][46][47] AKT PI3K-AKT directly or in crosstalk with other signaling pathways can induce EMT [48,49]. Drugs inhibiting EMT via the Akt/GSK-3β/Snail pathway decrease the invasiveness of PCa cells [50] Implicated in PCa cell proliferation and resistance to apoptosis [51,52] Phosphorylated EGFR and PI3K/Akt signaling kinases detected in breast cancer patient CTCs [53], pERK/Akt pathway in CTCs in hepatocellular carcinoma patients [54], PTEN loss in circulating tumor cells in CRPC patients [55].…”

Resveratrol inhibits proliferation and promotes apoptosis via the androgen receptor splicing variant 7 and PI3K/AKT signaling pathway in LNCaP prostate cancer cells

“…The combination of androgens and AR induces the dissociation of AR from HSP90 and stimulates AR phosphorylation to activate the activity of downstream proteins (15). These proteins activate or inhibit target genes, which regulate the proliferation, survival and production of PSA in prostate cells (16).…”