Enhancer RNAs in Prostate Cancer

Noncoding enhancer RNAs (eRNAs) are a class of RNAs that do not encode protein, but still are functionally important. Dr. Huang's lab is investigating how eRNAs transcribed from prostate-specific antigen gene enhancers (PSA eRNAs) play an essential role in regulation of androgen receptor-mediated gene expression and androgen refractory growth of castration-resistant prostate cancer (CRPC) cells.

Prostate-specific antigen is one of the strongest genes regulated by androgen receptor. Its protein has been used as a biomarker for prostate cancer diagnosis and prognosis, but its biological role in prostate cancer is not established.

Androgen deprivation therapy has long been the mainstay of treatment for advanced prostate cancer, but tumors inevitably become CRPC. Reactivation of androgen receptor is a central mechanism for CRPC progression, but the molecular details remain unclear.

Targeting the androgen-androgen receptor axis with second-generation endocrine therapies such as abiraterone and enzalutamide has been effective initially for CRPC treatment in clinical practice. However, most patients develop resistance that undermines survival and quality of life. Resistance is likely due to expression of androgen receptor splice variants (AR-Vs) such as AR-V7 (also called AR3), other undefined mechanisms or a combination thereof. However, the molecular mechanism that drives AR-V7 expression also is largely unclear.

Importantly, both abiraterone and enzalutamide exert their action through the androgen receptor ligand binding domain. However, a major barrier to effective treatment is that no drug targets the androgen receptor beyond the ligand binding domain. Dr. Huang's research on how PSA eRNAs help regulate androgen receptor gene expression is aimed at development of such a drug.

The Cancer Epigenetics and Functional Genomics Lab's research on eRNAs in prostate cancer is supported in part by a Challenge Award from the Prostate Cancer Foundation.