Dihydrotestosterone induces p27 degradation via direct binding with SKP2 in ovarian and breast cancer

作者：Shi Pengcheng; Zhang Yan; Tong Xiaowen; Yang Yu; Shao Zhiming^*

来源：International Journal of Molecular Medicine, 2011, 28(1): 109-114.

DOI：10.3892/ijmm.2011.677

• dihydrotestosterone
• p27
• S-phase kinase-associated protein 2
• direct binding
• cell cycle
• ovarian and breast cancer

The effect of androgens on the prevention or promotion of cell cycle progression in ovarian and breast cancer is controversial. This effect determines the basic rules of how to treat postmenopausal patients properly after surgery. In the present study, we investigated the effects of different androgens, namely dihydrotestosterone (DHT), testosterone and dehydroepiandrosterone (DHEA) in MCF-7 breast cancer and OVCAR-3 ovarian cancer cells. We found that DHT could down-regulate p27, but not p21, within 4 h. Further studies proved that DHT induced p27 degradation through the ubiquitin-proteasome proteolytic pathway. Inhibition of the androgen receptor and of phosphorylation did not hamper the degradation. However, proteolysis inhibitors effectively antagonized the DHT-induced p27 degradation. Knockdown of the S-phase kinase-associated protein 2 (SKP2), rather than of the Kipl ubiquitination promoting complex 1 (KPC1), also prevented p27 clown-regulation. DHT led to the direct binding of p27 to SKP2 independent of the phosphorylation status. Collectively, DHT, but not the other examined androgens regulated the degradation of p27 in MCF-7 and OVCAR-3 cells. Furthermore, SKP2 was shown to act as a DHT receptor.

• 出版日期2011-7
• 单位同济大学; 复旦大学