Abstract
Androgen receptor (AR) is frequently over-expressed and plays a critical role in the growth and progression of human prostate cancer. The therapy attempting to target AR signalling was established in decades ago but the treatment of prostate cancer is far from being satisfactory. The assignable cause is that our understanding of the mechanism of AR regulation and re-activation remains incomplete. Increasing evidence suggests that deubiquitinases are involved in the regulation of cancer development and progression but the specific underlying mechanism often is not elucidated. In the current study, we have identified ubiquitin-specific protease 14 (USP14) as a novel regulator of AR, inhibiting the degradation of AR via deubiquitinating this oncoprotein in the androgen-responsive prostate cancer cells. We found that (i) USP14 could bind to AR, and additionally, both genetic and pharmacological inhibition of USP14 accelerated the ubiquitination and degradation of AR; (ii) downregulation or inhibition of USP14 suppressed cell proliferation and colony formation of LNcap cells and, conversely, overexpression of USP14 promoted the proliferation; and (iii) reduction or inhibition of USP14 induced G0/G1 phase arrest in LNcap prostate cancer cells. Hence, we conclude that USP14 promotes prostate cancer progression likely through stabilization of AR, suggesting that USP14 could be a promising therapeutic target for prostate cancer.
Highlights
Androgen receptor (AR) signalling pathway dominates the survival, proliferation and growth of prostate cancer
We verified that AR was highly expressed in the LNcap cells but it was hardly detectable in DU145 and PC3 cells (Figure 1a)
To corroborate that the IU1-induced cell growth inhibition depends on its inhibition of USP14, we applied USP14 small interfering RNA or short hairpin RNA to knock down USP14 expression, and tested the effect of USP14 knockdown on the cell viability of LNcap cells
Summary
Androgen receptor (AR) signalling pathway dominates the survival, proliferation and growth of prostate cancer. The ligand-activated AR binds to specific DNA sequences on the target genes and initiates expression of a series of genes that promote prostate cancer progression. DUBs remove ubiquitin (Ub) and ubiquitin-like (Ubl) chains from target proteins prior to their degradation and thereby participate in the regulation of multiple cellular processes, including cell cycle control,[10,11] DNA stabilization,[12,13,14] chromatin modification[15] and various cellular signalling pathways.[16] The human genome encodes approximately 100 putative DUBs, which are subdivided into six families on the basis of their sequences and structural differences. Overexpression of wild-type USP10 stimulated AR activity as revealed by reporter constructs
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