Escaping Enzalutamide: Malat1 Contributes to Resistance

RESEARCH HIGHLIGHTS

Nature Reviews Urology | Published online 6 Jun 2017; doi:10.1038/nrurol.2017.91

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