Effect of GGC (glycine) repeat length polymorphism in the human androgen receptor on androgen action

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Abstract
BACKGROUND The human androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeat length polymorphisms. Normal glutamine repeat length affects androgen action, but an effect of normal glycine repeat length has not been studied. METHODS To determine whether glycine/GGC repeat length affects AR function, we constructed AR cDNA expression vectors with different GGC repeat lengths in the physiological range (13–17 GGCs). AR constructs were transfected into AR-negative DU145 human prostate cancer cells along with an androgen-responsive reporter plasmid (PSA-firefly luciferase) and a transfection efficiency control plasmid (Renilla luciferase). RESULTS Glycine repeat length had no significant effect on androgen-dependent AR transactivation activity expressed as firefly luciferase per unit amount of AR protein. However, AR protein levels (normalized for transfection efficiency) were inversely affected by glycine repeat length (P < 0.001; r = −0.9; e.g., GGC13 yielded 2.7 times more AR protein than did GGC17). Therefore, the net amount of AR activity per cell would be higher in cells expressing AR with a short glycine repeat. Based on programs that predict structure from RNA sequence, the GGC repeat can form a hairpin structure, the free energy of which decreases (i.e., hairpin stability increases) as a function of increasing repeat length. This suggests that hairpin stability may interfere with translation, accounting for the inverse effect of GGC repeat length on AR protein yields. CONCLUSIONS The ability of a short GGC repeat to enhance androgen action provides a biologically plausible mechanism to account for reports that a short GGC repeat in the AR gene is a risk factor for prostate cancer.