Lavinia Casati, Fabio Celotti and Valeria Sibilia Pages 23 - 35 ( 13 )
Background: The importance of epigenetics in cancer is well known. Since many epigenetic mechanisms are involved in cancer progression, they may represent a target for a new pharmacological approach. Prostate cancer is the most common malignancy in men. After failure of the androgen deprivation therapy, the recurrent disease is termed castration- resistant cancer (CRPC). Since CRPC remains an incurable disease, new studies are focusing on the mechanisms critical for CRPC development, to identify new pharmacological targets.
Methods: A MEDLINE research related to CRPC and epigenome has been carried out.
Results: CRPC is probably due to several genetic and epigenetic mechanisms involved in AR activation, even in the presence of low androgen levels. Increasing evidence suggests that an aberrant DNA methylation may promote CRPC progression, augmenting genomic instability. Deregulated miRNAs are involved in initiation, progression, and metastatization of prostate cancers. MiRNAs may act like oncogenes (oncomirs) which can promote cancer progression, or tumor suppressors (anti-oncomirs) which inhibit CRPC progression. miRNA replacement therapy represents the most promising anticancer strategy, however only MRX34 (a doublestranded RNA mimic of the anti-oncomir, miR-34) has reached phase I clinical trial. Also, the deregulation of long non coding RNAs (lncRNAs) has been involved in CRPC development and lncRNAs may gain diagnostic/ therapeutic relevance. Recently research was focused on the chromatin reader proteins containing bromodomain and extraterminal domain (BET family). Since BET inhibitors act downstream of AR, these compounds might be effective in a condition of mediated AR resistance to androgen deprivation.
Conclusions: The recent finding about CRPC epigenome might provide several emerging treatment strategies to counteract efficiently the tumor progression.
Epigenetic, CRPC, androgen receptor, ncRNA, pharmacological approach, BET therapy.
Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy.