Abstract
Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479-90. ©2017 AACR.
Highlights
Androgen receptor (AR) is highly expressed in prostate cancer cells and transactivates target genes that play essential role in tumour development and progression [1, 2]
We identified LSD1-mediated epigenetic reprogramming in castration-resistant prostate cancer (CRPC), which activates a group of cell-cycle genes, including CENPE, to drive prostate cancer progression
To explore the role of LSD1 in the progression to CRPC, we investigated the function of LSD1 in LNCaP, the canonical androgen-dependent (AD) prostate cancer cell line, and abl, an androgen-independent derivative of LNCaP cells
Summary
Androgen receptor (AR) is highly expressed in prostate cancer cells and transactivates target genes that play essential role in tumour development and progression [1, 2]. The recent clinical success of abiraterone (a CYP17A1 inhibitor that further suppresses androgen synthesis) and enzalutamide (a secondgeneration AR antagonist) has confirmed that AR signaling is a key driver of tumor progression in CRPC [3,4,5]. These agents can only retard disease progression, and patients undergoing ADT generally relapse within 1 to 2 years. Developing novel therapeutic options are in urgent need for the treatment of CRPC patients
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