American Association for Cancer Research
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Data Supplement from AR-Regulated TWEAK-FN14 Pathway Promotes Prostate Cancer Bone Metastasis

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posted on 2023-03-30, 22:25 authored by JuanJuan Yin, Yen-Nien Liu, Heather Tillman, Ben Barrett, Stephen Hewitt, Kris Ylaya, Lei Fang, Ross Lake, Eva Corey, Colm Morrissey, Robert Vessella, Kathleen Kelly

Supplemental Figure 4. (A) AR activity signature genes expressed as a summed Z score in metastatic samples separated on the basis of Fn14 expression above the median (Fn14 high) or below the median (Fn14 low) using the Grasso dataset. * p<0.05. (B) qChIP analysis was performed in DU145 cells expressing doxycycline induced AR. AR binding to the predicted AREs in the Fn14 promoter was determined either with or without prior DHT (5nM) treatment for 4 hours. The binding activity to each site is given as a percentage of total input then normalized to individual immunoglobulin G (IgG). (C) FACS analysis of human Fn14 promoter reporter in DU145 cells expressing Tet-on TA and TREG3-AR with or without prior doxycycline and DHT treatment.



The recurrence of prostate cancer metastases to bone after androgen deprivation therapy is a major clinical challenge. We identified FN14 (TNFRSF12A), a TNF receptor family member, as a factor that promotes prostate cancer bone metastasis. In experimental models, depletion of FN14 inhibited bone metastasis, and FN14 could be functionally reconstituted with IKKβ-dependent, NFκB signaling activation. In human prostate cancer, upregulated FN14 expression was observed in more than half of metastatic samples. In addition, FN14 expression was correlated inversely with androgen receptor (AR) signaling output in clinical samples. Consistent with this, AR binding to the FN14 enhancer decreased expression. We show here that FN14 may be a survival factor in low AR output prostate cancer cells. Our results define one upstream mechanism, via FN14 signaling, through which the NFκB pathway contributes to prostate cancer metastasis and suggest FN14 as a candidate therapeutic and imaging target for castrate-resistant prostate cancers. Cancer Res; 74(16); 4306–17. ©2014 AACR.