The NLR-related protein NWD1 is associated with prostate cancer and modulates androgen receptor signaling

Ricardo G. Correa*, Maryla Krajewska, Carl F. Ware, Motti Gerlic, John C. Reed

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Prostate cancer (PCa) is among the leading causes of cancer-related death in men. Androgen receptor (AR) signaling plays a seminal role in prostate development and homeostasis, and dysregulation of this pathway is intimately linked to prostate cancer pathogenesis and progression. Here, we identify the cytosolic NLR-related protein NWD1 as a novel modulator of AR signaling. We determined that expression of NWD1 becomes elevated during prostate cancer progression, based on analysis of primary tumor specimens. Experiments with cultured cells showed that NWD1 expression is up-regulated by the sex-determining region Y (SRY) family proteins. Gene silencing procedures, in conjunction with transcriptional profiling, showed that NWD1 is required for expression of PDEF (prostate-derived Ets factor), which is known to bind and co-regulate AR. Of note, NWD1 modulates AR protein levels. Depleting NWD1 in PCa cell lines reduces AR levels and suppresses activity of androgendriven reporter genes. NWD1 knockdown potently suppressed growth of androgendependent LNCaP prostate cancer cells, thus showing its functional importance in an AR-dependent tumor cell model. Proteomic analysis suggested that NWD1 associates with various molecular chaperones commonly related to AR complexes. Altogether, these data suggest a role for tumor-associated over-expression of NWD1 in dysregulation of AR signaling in PCa.

Original languageEnglish
Pages (from-to)1666-1682
Number of pages17
JournalOncotarget
Volume5
Issue number6
DOIs
StatePublished - 2014

Funding

FundersFunder number
National Institutes of HealthR01 CA164679, P01 CA177322, R01 AI056324, U01 CA114810
National Cancer InstituteP01CA177322

    Keywords

    • AR
    • NLR
    • PDEF
    • Prostate
    • SRY

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