Int J Biol Sci 2021; 17(13):3288-3304. doi:10.7150/ijbs.63300 This issue

Research Paper

The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer

Yongjun Quan1, Xiaodong Zhang2, William Butler3, Zhen Du1, Mingdong Wang1, Yuexin Liu1, Hao Ping1,✉

1. Department of Urology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
2. Department of Urology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China.
3. Department of Pathology, Duke University School of Medicine, Durham NC 27710, USA.

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Citation:
Quan Y, Zhang X, Butler W, Du Z, Wang M, Liu Y, Ping H. The role of N-cadherin/c-Jun/NDRG1 axis in the progression of prostate cancer. Int J Biol Sci 2021; 17(13):3288-3304. doi:10.7150/ijbs.63300. Available from https://www.ijbs.com/v17p3288.htm

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Abstract

Graphic abstract

The dysregulation of androgen receptor (AR) signaling is a critical event in the progression of prostate cancer (PCa) and hormone therapy consisting of androgen deprivation (ADT) or AR inhibition is therefore used to treat advanced cases. It is known that N-cadherin becomes upregulated following ADT and can directly induce PCa transformation to the castration-resistant stage (CRPC). However, the relationship between AR and N-cadherin is unclear and may promote better understanding of CRPC pathogenesis and progression. Here, we demonstrate a new axis of N-cadherin/c-Jun/N-myc downstream regulated gene 1 (NDRG1) that N-cadherin promotes c-Jun expression and suppresses NDRG1 to promote invasion and migration of PCa cells through epithelial to mesenchymal transition (EMT). Targeting N-cadherin in combination with enzalutamide (ENZ) treatment synergistically suppressed PC3 cell proliferation in vivo and in vitro. Further studies showed that compared to lower Gleason score (GS) (GS < 7) cases, high GS (GS > 7) cases exhibited elevated N-cadherin expression and reduced NDRG1 expression, corroborating our in vitro observations. We further demonstrate that c-Jun, AR, and DNA methyltransferase-1 (DNMT1) form a complex in the 12-O-tetradecanoyl phorbol-13-acetate (TPA) response elements (TREs) region of the NDRG1 promoter, which suppresses NDRG1 transcription through DNA hypermethylation. In conclusion, we demonstrate an underlying mechanism for how N-cadherin collaborates with AR and NDRG1 to promote CRPC progression. Controlling N-cadherin/c-Jun/NDRG1 axis may help to overcome resistance to commonly used hormone therapy to improve long-term patient outcomes.

Keywords: prostate cancer, N-cadherin, androgen receptor, NDRG1, c-Jun, DNA methylation, enzalutamide