Abstract
The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER-associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD. Here, we describe that ERAD pathway is regulated by androgen, where its inhibitor SVIP was downregulated, all other ERAD genes were upregulated. Consistently, androgen treatment increased the degradation rate of ERAD substrates. Using several independent techniques, we showed that this regulation is through androgen receptor transactivation. ERAD genes found to be upregulated in prostate cancer tissues and silencing expression of Hrd1, SVIP, and gp78 reduced the in vitro migration and malignant transformation of LNCaP cells. Our data suggests that expression levels of ERAD components are regulated by androgens, that promotes ERAD proteolytic activity, which is positively related with prostate tumorigenesis.
Highlights
IntroductionUnderstanding the regulation of ER-associated degradation (ERAD) is one of the main questions of cellular proteostasis
Understanding the regulation of endoplasmic reticulum (ER)-associated degradation (ERAD) is one of the main questions of cellular proteostasis
We showed that ERAD is an androgen-regulated process where both the mRNA and protein levels of ERAD components are regulated with the treatment of the synthetic androgen, R1881
Summary
Understanding the regulation of ERAD is one of the main questions of cellular proteostasis. Since the previously characterized ERAD inhibitor SVIP found to be negatively regulated by androgen treatment in LNCaP cells, we were prompted to test regulation of ERAD pathway by androgen. We found that while the level of SVIP, the endogenous ERAD inhibitor, is decreased, all other tested ERAD proteins are increased by the R1881 treatment. This pattern is present in androgen sensitive prostate cancer cells, namely LNCaP and 22RV1, but not in androgen insensitive prostate cancer cells, PC3 and DU145. Consistent with androgen-mediated regulation of ERAD genes, R1881 treatment increases ERAD proteolytic activity since the degradation rate of two ERAD substrates, CD3δand KAI1. The effect of Hrd[1], gp, and SVIP was evaluated on the cell proliferation rate, wound healing, migration and malignant transformation of LNCaP cells using the RNAi approach, and our data suggests that ERAD may be involved in in vitro migration and malignant transformation in LNCaP cells
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