The long noncoding RNA (lncRNA) Malat1 contributes to enzalutamide resistance in castration-resistant prostate cancer (CRPC) by promoting the expression of the androgen receptor (AR) splice variant AR-V7. Targeting Malat1 could be of therapeutic benefit to men with this disease.
AR-V7 expression in circulating tumour cells (CTCs) is associated with resistance to the antiandrogen enzalutamide. To investigate the possible mechanisms of this resistance, Wang and colleagues developed enzalutamide-resistant prostate cancer cells and analysed the expression of 32 lncRNAs. Expression of Malat1, a lncRNA with upregulated expression in CRPC, was increased in these cells, along with AR-V7 expression. Induction of Malat1 expression resulted in increased AR-V7 expression and altered expression of AR-V7-regulated genes. Furthermore, treatment with Malat1 small interfering RNA reversed these effects. Knock down of AR or treatment of cells with enzalutamide in the presence of 1 nmol/l concentrations of dihydrotestosterone (DHT) increased Malat1 expression, whereas functional AR-complementary DNA or DHT treatment suppressed expression. Increased Malat1 expression reduced the effects of enzalutamide treatment on cell growth and knock down of Malat1 reversed enzalutamide resistance in enzalutamide-resistant cells.
AR bound to the AR response elements on the proximal promoter of Malat1. AR binding was increased by DHT treatment and reduced by enzalutamide treatment. Furthermore, DHT suppressed H3K4me3 levels in the Malat1 promoter, whereas enzalutamide increased them.
In enzalutamide-resistant cells, binding of Malat1 and AR to pre-mRNA-splicing factor SF2 (SF2) was increased and SF2 activity was also elevated. Knock down of SF2 reduced AR-V7 expression. Suppression of AR-V7 or SH2 resulted in a reversal of enzalutamide resistance mediated by Malat1.
Knock down of Malat1 resulted in decreased AR-V7 levels. Moreover, treatment of enzalutamide-resistant cells with Malat1 siRNA or ASC-J9, an AR-V7 degradation enhancer, suppressed their growth. In vivo, enzalutamide-resistant xenografts treated with either Malat1 siRNA or ASC-J9 had substantially reduced growth.
In patients, CTCs from men with metastatic CRPC showed an increase in Malat1 and AR-V7 expression after enzalutamide treatment and analysis of data fromThe Cancer Genome Atlas showed men with increased Malat1 expression had poor overall survival.
Together these data suggest that developing novel drugs that target the Malat1–AR-V7 axis is a potential therapeutic option for enzalutamide-resistant CRPC.
Wang, R. et al. Preclinical study using Malat1 small interfering RNA or androgen receptor splicing variant 7 degradation enhancer ASC-J9® to suppress enzalutamide-resistant prostate cancer progression. Eur. Urol. http://dx.doi.org/10.1016/j.eururo.2017.04.005 (2017)
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Stone, L. Escaping enzalutamide: Malat1 contributes to resistance. Nat Rev Urol 14, 450 (2017). https://doi.org/10.1038/nrurol.2017.91
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