title: NF-κB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer.
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.
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California. acgao@ucdavis.edu nnadiminty@ucdavis.edu.
authors.forename: Nagalakshmi
authors.initials: N
authors.lastname: Nadiminty
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Ramakumar
authors.initials: R
authors.lastname: Tummala
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Chengfei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California.
authors.forename: Wei
authors.initials: W
authors.lastname: Lou
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California. Comprehensive Cancer Center, University of California at Davis, Sacramento, California.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Evans
authors.affiliation: Department of Urology, University of California at Davis, Sacramento, California. Comprehensive Cancer Center, University of California at Davis, Sacramento, California. acgao@ucdavis.edu nnadiminty@ucdavis.edu.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Gao
mesh_terms: D017398:Alternative Splicing; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D022821:RNA Splice Sites; D011944:Receptors, Androgen / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D052003:NF-kappa B p52 Subunit; D009570:Nitriles; D016271:Proto-Oncogene Proteins c-myc; D012322:RNA Precursors; D022821:RNA Splice Sites; D011944:Receptors, Androgen; C000619656:hnRNPA1 protein, human; D010669:Phenylthiohydantoin; C540278:enzalutamide