Blockade of the AR CE3 PAS inhibits AR-V expression. A. Schematic of predicted AR
RNA-seq coverage based on use of annotated splice junctions and PASs in AR
cryptic exons (CEs). B. Observed AR RNA-seq coverage from 22Rv1 and metastatic
biopsies (top) consistent with a new model wherein multiple AR-Vs arise from use
of multiple splice acceptor sites that terminate at a single PAS (bottom). The
location at which CE3 pAM morpholino binds to induce steric blockade is shown.
C. Left panels: 22Rv1-undup3 (top) and 22Rv1 (bottom) cells were transfected
with 10 μM control or CE3-pAM. Mean mRNA fold change of AR and AR-Vs
relative to actin control is shown (n=6, error bars=95%
confidence intervals). **** p≤0.0001,
unpaired t-tests. Right panels: Western blot of lysates from transfected cells,
probed with antibodies to AR NTD or ERK-2 (loading control). D. Crystal violet
staining to assess growth of 22Rv1-undup3 (left) and 22Rv1 (right) cells
transfected as in panel C maintained in androgen-deplete medium (CSS) in the
presence of 1 nM DHT or vehicle control (ethanol). Data points represent means
(n=6, 22Rv1-undup1, n=4, 22Rv1; error bars = 95%
confidence intervals). **** p≤ 0.0001,
** p ≤ 0.01, ns p>0.05 p-values in a two-tailed
t-test.