Trihydrophobin Promote The Degradation Of Androgen Receptor And Its Role In The Progression Of Breast Cancer Research

The androgen-signaling pathway plays critical roles in normal prostate development, benign prostatic hyperplasia, established prostate cancer, and in prostate carcinogenesis. In this study, we report that trihydrophobin 1 (TH1) is a potent negative regulator to attenuate the androgen signal-transduction cascade through promoting androgen receptor (AR) degradation. TH1 interacts with AR both in vitro and in vivo, decreases the stability of AR, and promotes AR ubiquitination in a ligand-independent manner. TH1 also associates with AR at the active androgen-responsive prostate-specific antigen (PSA) promoter in the nucleus of LNCaP cells. Decrease of endogenous AR protein by TH1 interferes with androgen-induced luciferase reporter expression and reduces endogenous PSA expression. Taken together, these results indicate that TH1 is a novel regulator to control the duration and magnitude of androgen signal transduction and might be directly involved in androgen-related developmental, physiological, and pathological processes. Trihydrophobin 1 (TH1) is a member of negative elongation factors (NELF) complex, which is involved in transcriptional pausing. Although NELF complex attenuates the estrogen receptor a-mediated transcription, little is known about the relationship between TH1 and tumor progression. Here, we reported that protein level of TH1 was negatively correlated with the malignancy of human breast cancer. Immunohistochemical analysis revealed that TH1 expression in clinical stage III-IV primary breast cancer tissues was statistically significantly lower than that in stage I-II breast tissues (P<0.01), and especially inversely associated with lymph node metastasis (P<0.001). Furthermore, we demonstrated that overexpression of TH1 in MDA-MB-231 cells inhibited and knockdown of TH1 in MCF-7 cells enhanced cell migratory ability of breast cancer cells. Moreover, upregulation of TH1 in MDA-MB-231 cells resulted in the decrease of cell cycle protein cyclin D1,β-catenin and ERK activity, and the increase of cyclin-dependent kinase inhibitor p21. In contrast, knockdown of TH1 in MCF-7 cells enhanced the expression of cyclin D1 andβ-catenin, increased the activity of ERK, and downregulated the expression of p21. Additionally, overexpression of TH1 in MDA-MB-231 cells prevented and, however, knockdown of TH1 in MCF-7 cells induced epithelial-mesenchymal transition (EMT) in breast cancer cells. Taken together, our results suggest that TH1 might play an important role in regulation of proliferation and invasion in human breast cancer, and thereby might be a potential target for human breast cancer treatment.