TY - JOUR
T1 - Inhibiting Multiple Deubiquitinases to Reduce Androgen Receptor Expression in Prostate Cancer Cells
AU - de Las Pozas, Alicia
AU - Reiner, Teresita
AU - De Cesare, Virginia
AU - Trost, Matthias
AU - Perez-Stable, Carlos
N1 - Tis work was supported by a Veterans Afairs BLR&D Merit Review grant (#086906) to CPS. We thank Drs.
Guy Howard, Hermes Florez, and Bernard Roos for support, Kerry Burnstein and Bal Lokeshwar for providing
cells, and Gaetan Delcroix for reviewing manuscript. We also thank the DNA cloning, protein production, DNA
sequencing facility, and mass spectrometry teams of the MRC Protein Phosphorylation and Ubiquitylation Unit
for support. MT was funded by Medical Research Council UK (MC_UU_12016/5) and the pharmaceutical
companies supporting the Division of Signal Transduction Therapy (DSTT) (Boehringer-Ingelheim,
GlaxoSmithKline, and Merck KGaA).
PY - 2018/9/3
Y1 - 2018/9/3
N2 - Prostate cancer (PCa), a leading cause of cancer-related death in men, becomes resistant to androgen deprivation therapy by inducing androgen receptor (AR) activity, which is known as castration-resistant PCa (CRPC). Enzalutamide is an approved drug that inhibits AR activity and increases overall survival. However, resistance to enzalutamide develops rapidly often by increasing AR activity, suggesting that new therapies are required for CRPC. We investigated whether betulinic acid (BA), a small molecule from plants that inhibits multiple deubiquitinases (DUBs), reduces AR, and selectively kills PCa cells, can provide an adjuvant strategy for CRPC. Our data indicated that BA reduced AR protein stability and mRNA expression, making it an attractive agent for CRPC. BA decreased AR mRNA possibly by inhibiting a histone 2A DUB thereby increasing ubiquitinated histone 2A, a transcriptional repressor. We identified multiple and specific DUBs inhibited by BA either in PCa cells or using recombinant DUBs. Similar results were obtained using another multi-DUB inhibitor WP1130, suggesting that these DUB inhibitors can decrease AR expression and increase PCa-specific death. Our results also suggest that combining multi-DUB inhibitors BA or WP1130 with enzalutamide may provide a novel strategy for CRPC by further decreasing AR expression and increasing apoptotic cell death.
AB - Prostate cancer (PCa), a leading cause of cancer-related death in men, becomes resistant to androgen deprivation therapy by inducing androgen receptor (AR) activity, which is known as castration-resistant PCa (CRPC). Enzalutamide is an approved drug that inhibits AR activity and increases overall survival. However, resistance to enzalutamide develops rapidly often by increasing AR activity, suggesting that new therapies are required for CRPC. We investigated whether betulinic acid (BA), a small molecule from plants that inhibits multiple deubiquitinases (DUBs), reduces AR, and selectively kills PCa cells, can provide an adjuvant strategy for CRPC. Our data indicated that BA reduced AR protein stability and mRNA expression, making it an attractive agent for CRPC. BA decreased AR mRNA possibly by inhibiting a histone 2A DUB thereby increasing ubiquitinated histone 2A, a transcriptional repressor. We identified multiple and specific DUBs inhibited by BA either in PCa cells or using recombinant DUBs. Similar results were obtained using another multi-DUB inhibitor WP1130, suggesting that these DUB inhibitors can decrease AR expression and increase PCa-specific death. Our results also suggest that combining multi-DUB inhibitors BA or WP1130 with enzalutamide may provide a novel strategy for CRPC by further decreasing AR expression and increasing apoptotic cell death.
UR - http://www.scopus.com/inward/record.url?scp=85052644871&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-31567-3
DO - 10.1038/s41598-018-31567-3
M3 - Article
C2 - 30177856
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 13146
ER -