LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models

Cancer Cell International
Sergio Regufe da MotaSimon J Crabb

Abstract

Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Furth...Continue Reading

References

Feb 16, 2002·Methods : a Companion to Methods in Enzymology·K J Livak, T D Schmittgen
Sep 6, 2005·Molecular Cell·Yu-Jiang ShiYang Shi
Nov 17, 2007·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Mari KaarbøFahri Saatcioglu
Sep 10, 2009·The Prostate·Jörg EllingerAlexander von Ruecker
Sep 8, 2010·The New England Journal of Medicine·Philip W KantoffUNKNOWN IMPACT Study Investigators
Mar 5, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Gerhardt AttardJohann S de Bono
Mar 9, 2011·Bioorganic & Medicinal Chemistry·Hanae BenelkebirA Ganesan
May 27, 2011·Acta Oncologica·Saroj Niraula, Ian F Tannock
May 27, 2011·The New England Journal of Medicine·Johann S de BonoUNKNOWN COU-AA-301 Investigators
Aug 17, 2012·The New England Journal of Medicine·Howard I ScherUNKNOWN AFFIRM Investigators
Dec 12, 2012·The New England Journal of Medicine·Charles J RyanUNKNOWN COU-AA-302 Investigators
Jul 19, 2013·Pharmacology & Therapeutics·Ayesha A ShafiNancy L Weigel
Jul 19, 2013·The New England Journal of Medicine·C ParkerUNKNOWN ALSYMPCA Investigators
Sep 5, 2013·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Dana E RathkopfHoward I Scher
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Jun 3, 2014·The New England Journal of Medicine·Tomasz M BeerUNKNOWN PREVAIL Investigators
Jul 23, 2014·Hormones & Cancer·Mary NakazawaJun Luo
Sep 4, 2014·The New England Journal of Medicine·Emmanuel S AntonarakisJun Luo
Sep 17, 2014·Nature Reviews. Urology·Frank ClaessensSteven Joniau
Jan 30, 2015·International Urology and Nephrology·Min WangXiaodong Weng
Sep 22, 2016·Clinical Epigenetics·Inês GraçaCarmen Jerónimo
Apr 1, 2017·Current Oncology Reports·Panagiotis J VlachostergiosHimisha Beltran
Feb 9, 2018·The New England Journal of Medicine·Matthew R SmithUNKNOWN SPARTAN Investigators

❮ Previous
Next ❯

Citations

Dec 7, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Guan-Jun YangChung-Hang Leung
Dec 16, 2020·Experimental & Molecular Medicine·Bruno PerilloAntimo Migliaccio
Feb 11, 2021·Molecular Cancer Therapeutics·Bradleigh WhittonSimon J Crabb
May 7, 2021·Endocrine Reviews·Lucie MalbeteauMuriel Le Romancer

❮ Previous
Next ❯

Methods Mentioned

BETA
Assay
transfection
immunoprecipitation
PCR

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.