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NF-κB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer
Article (Web of Science)
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abstract
Abstract
Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation antiandrogens such as enzalutamide. Here, we demonstrate that the splicing factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in the generation of AR splice variants such as AR-V7. hnRNPA1 is overexpressed in prostate tumors compared with benign prostates, and its expression is regulated by NF-κB2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-κB2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and AR-V7 are positively correlated with each other in prostate cancer. The regulatory circuit involving NF-κB2/p52, c-Myc, and hnRNPA1 plays a central role in the generation of AR splice variants. Downregulation of hnRNPA1 and consequently of AR-V7 resensitizes enzalutamide-resistant cells to enzalutamide, indicating that enhanced expression of hnRNPA1 may confer resistance to AR-targeted therapies by promoting the generation of splice variants. These findings may provide a rationale for cotargeting these pathways to achieve better efficacy through AR blockade. Mol Cancer Ther; 14(8); 1884–95. ©2015 AACR.
authors
Nadiminty, Nagalakshmi
Tummala, Ramakumar
Liu, Chengfei
Lou, Wei
Evans, Christopher P.
Gao, Allen C.
publication date
2015
webpage
http://dx.doi.org/10.1158/1535-7163.mct-14-1057
published in
MOLECULAR CANCER THERAPEUTICS
Journal
Additional Document Info
number of pages
11
start page
1884
end page
1895
volume
14
issue
8