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dc.contributor.author
Paschalis, Alec
dc.contributor.author
Alimonti, Andrea
dc.contributor.author
et al.
dc.date.accessioned
2021-03-16T07:05:00Z
dc.date.available
2021-03-16T03:53:58Z
dc.date.available
2021-03-16T07:05:00Z
dc.date.issued
2021-02
dc.identifier.issn
0008-5472
dc.identifier.issn
1538-7445
dc.identifier.other
10.1158/0008-5472.CAN-20-1807
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/474711
dc.description.abstract
Endocrine resistance (EnR) in advanced prostate cancer is fatal. EnR can be mediated by androgen receptor (AR) splice variants, with AR splice variant 7 (AR-V7) arguably the most clinically important variant. In this study, we determined proteins key to generating AR-V7, validated our findings using clinical samples, and studied splicing regulatory mechanisms in prostate cancer models. Triangulation studies identified JMJD6 as a key regulator of AR-V7, as evidenced by its upregulation with in vitro EnR, its downregulation alongside AR-V7 by bromodomain inhibition, and its identification as a top hit of a targeted siRNA screen of spliceosome-related genes. JMJD6 protein levels increased (P < 0.001) with castration resistance and were associated with higher AR-V7 levels and shorter survival (P = 0.048). JMJD6 knockdown reduced prostate cancer cell growth, AR-V7 levels, and recruitment of U2AF65 to AR pre-mRNA. Mutagenesis studies suggested that JMJD6 activity is key to the generation of AR-V7, with the catalytic machinery residing within a druggable pocket. Taken together, these data highlight the relationship between JMJD6 and AR-V7 in advanced prostate cancer and support further evaluation of JMJD6 as a therapeutic target in this disease. © 2021 American Association for Cancer Research
en_US
dc.language.iso
en
en_US
dc.publisher
American Association for Cancer Research
en_US
dc.title
JMJD6 Is a druggable oxygenase that regulates AR-V7 expression in prostate cancer
en_US
dc.type
Journal Article
dc.date.published
2021-02-15
ethz.journal.title
Cancer Research
ethz.journal.volume
81
en_US
ethz.journal.issue
4
en_US
ethz.journal.abbreviated
Cancer Res
ethz.pages.start
1087
en_US
ethz.pages.end
1100
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
Philadelphia, PA
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::09703 - Alimonti, Andrea / Alimonti, Andrea
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02070 - Dep. Gesundheitswiss. und Technologie / Dep. of Health Sciences and Technology::02540 - Institut für Translationale Medizin / Institute of Translational Medicine::09703 - Alimonti, Andrea / Alimonti, Andrea
ethz.date.deposited
2021-03-16T03:54:08Z
ethz.source
SCOPUS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-03-16T07:05:15Z
ethz.rosetta.lastUpdated
2021-03-16T07:05:15Z
ethz.rosetta.exportRequired
true
ethz.rosetta.versionExported
true
ethz.COinS
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