NF-κB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer
Nagalakshmi Nadiminty,Ramakumar Tummala,Chengfei Liu,Wei Lou,Christopher P. Evans,Allen C. Gao +5 more
TLDR
It is demonstrated 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, which may provide a rationale for cotargeting these pathways to achieve better efficacy through AR blockade.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 anti-androgens 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 to benign prostates and its expression is regulated by NF-kappaB2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-kappaB2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and of AR-V7 are positively correlated with each other in PCa. The regulatory circuit involving NF-kappaB2/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 co-targeting these pathways to achieve better efficacy through AR blockade.read more
Citations
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Roles and mechanisms of alternative splicing in cancer - implications for care.
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Inhibition of de novo lipogenesis targets androgen receptor signaling in castration-resistant prostate cancer
Giorgia Zadra,Caroline F. Ribeiro,Paolo Chetta,Paolo Chetta,Yeung Ho,Stefano Cacciatore,Stefano Cacciatore,Xueliang Gao,Sudeepa Syamala,Clyde Bango,Cornelia Photopoulos,Ying Huang,Svitlana Tyekucheva,Débora Campanella Bastos,Jeremy Tchaicha,Brian Lawney,Takuma Uo,Laura D’Anello,Alfredo Csibi,Radha L. Kalekar,Benjamin Larimer,Leigh Ellis,Leigh Ellis,Lisa M. Butler,Lisa M. Butler,Colm Morrissey,Karen McGovern,Vito J. Palombella,Jeffery L. Kutok,Umar Mahmood,Silvano Bosari,Julian Adams,Stephane Peluso,Scott M. Dehm,Stephen R. Plymate,Massimo Loda,Massimo Loda +36 more
TL;DR: It is demonstrated that selective FASN inhibition antagonizes CRPC growth through metabolic reprogramming and results in reduced protein expression and transcriptional activity of both full-length AR (AR-FL) and AR-V7, which offers a therapeutic opportunity for mCRPC and a potential mechanism to overcome resistance to AR inhibitors.
Journal ArticleDOI
Androgen receptor variant-driven prostate cancer: clinical implications and therapeutic targeting
TL;DR: Initial clinical studies have now shown that certain AR-Vs, in particular AR-V7, may be associated with resistance to abiraterone and enzalutamide but not taxane chemotherapies when detected in circulating tumor cells.
Journal ArticleDOI
Alternative splicing in prostate cancer
Alec Paschalis,Adam Sharp,Jonathan Welti,Antje Neeb,Ganesh V. Raj,Jun Luo,Stephen R. Plymate,Johann S. de Bono +7 more
TL;DR: The authors outline the current understanding of the role of the spliceosome in prostate cancer progression and explore the therapeutic utility of manipulating alternative splicing to improve patient care.
Journal ArticleDOI
Aberrant RNA Splicing in Cancer and Drug Resistance
Bi-Dar Wang,Norman H. Lee +1 more
TL;DR: To overcome drug resistance, opportunities for developing novel strategies to specifically target the aberrant splicing variants or splicing machinery that generates the splice variants are discussed.
References
More filters
Journal ArticleDOI
Epithelial-Mesenchymal Transitions in Development and Disease
Jean Paul Thiery,Jean Paul Thiery,Hervé Acloque,Ruby Yun-Ju Huang,Ruby Yun-Ju Huang,M. Angela Nieto +5 more
TL;DR: The mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
Journal ArticleDOI
Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing
TL;DR: It is estimated that transcripts from ∼95% of multiexon genes undergoAlternative splicing and that there are ∼100,000 intermediate- to high-abundance alternative splicing events in major human tissues.
Journal ArticleDOI
Gene expression correlates of clinical prostate cancer behavior.
Dinesh Singh,Phillip G. Febbo,Phillip G. Febbo,Kenneth N. Ross,Donald G. Jackson,Judith Manola,Christine Ladd,Pablo Tamayo,Andrew A. Renshaw,Anthony V. D'Amico,Jerome P. Richie,Eric S. Lander,Massimo Loda,Philip W. Kantoff,Todd R. Golub,William R. Sellers +15 more
TL;DR: The results support the notion that the clinical behavior of prostate cancer is linked to underlying gene expression differences that are detectable at the time of diagnosis.
Journal ArticleDOI
Gene expression profiling identifies clinically relevant subtypes of prostate cancer
Jacques Lapointe,Chunde Li,John P. Higgins,Matt van de Rijn,Eric Bair,Kelli Montgomery,Michelle Ferrari,Lars Egevad,Walter Rayford,Ulf S.R. Bergerheim,Peter Ekman,Angelo M. DeMarzo,Robert Tibshirani,David Botstein,Patrick O. Brown,James D. Brooks,Jonathan R. Pollack +16 more
TL;DR: It is suggested that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor subtypes may provide a basis for improved prognostication and treatment stratification.
Journal ArticleDOI
Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer
Rong Hu,Thomas A. Dunn,Shuanzeng Wei,Sumit Isharwal,Robert W. Veltri,Elizabeth B. Humphreys,Misop Han,Alan W. Partin,Robert L. Vessella,William B. Isaacs,G. Steven Bova,Jun Luo +11 more
TL;DR: Novel forms of AR alteration that are prevalent in HRPC are reported, suggesting a novel mechanism for the development of HRPC that warrants further investigation and may be explored as potential biomarkers and therapeutic targets for advanced PCa.
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