Nucleolin represses transcription of the androgen receptor gene through a G-quadruplex
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Cindy K. Miranti1,2, Sara Moore3, Yongeun Kim4, Venkateshwar Reddy Chappeta4, Kui Wu4, Biswanath De4, Vijay Gokhale5, Laurence H. Hurley1,4,5 and Elsa M. Reyes-Reyes1,2,3
1 University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
2 Department of Cellular and Molecular Medicine, Tucson, AZ 85724, USA
3 University of Arizona College of Medicine, Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Tucson, AZ 85724, USA
4 College of Pharmacy, University of Arizona, Tucson, AZ 85724, USA
5 BIO5 Institute, University of Arizona, Tucson, AZ 85724, USA
|Elsa M. Reyes-Reyes,||email:||firstname.lastname@example.org|
Keywords: prostate cancer; androgen receptor; nucleolin; gene repression; G-quadruplex
Received: October 29, 2019 Accepted: April 14, 2020 Published: May 12, 2020
The androgen receptor (AR) is a major driver of prostate cancer development and progression. Men who develop advanced prostate cancer often have long-term cancer control when treated with androgen-deprivation therapies (ADT). Still, their disease inevitably becomes resistant to ADT and progresses to castration-resistant prostate cancer (CRPC). ADT involves potent competitive AR antagonists and androgen synthesis inhibitors. Resistance to these types of treatments emerges, primarily through the maintenance of AR signaling by ligand-independent activation mechanisms. There is a need to find better ways to block AR to overcome CRPC. In the findings reported here, we demonstrate that the nuclear scaffold protein, nucleolin (NCL), suppresses the expression of AR. NCL binds to a G-rich region in the AR promoter that forms a G-quadruplex (G4) structure. Binding of NCL to this G4-element is required for NCL to suppress AR expression, specifically in AR-expressing tumor cells. Compounds that stabilize G4 structures require NCL to associate with the G4-element of the AR promoter in order to decrease AR expression. A newly discovered G4 compound that suppresses AR expression demonstrates selective killing of AR-expressing tumor cells, including CRPC lines. Our findings raise the significant possibility that G4-stabilizing drugs can be used to increase NCL transcriptional repressor activity to block AR expression in prostate cancer. Our studies contribute to a clearer understanding of the mechanisms that control AR expression, which could be exploited to overcome CRPC.
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