Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells
Menée in vitro et in vivo sur des modèles de cancer de la prostate, cette étude met en évidence des mécanismes par lesquels JMJD1A, une histone déméthylase, favorise la formation du variant d'épissage du récepteur des androgènes AR-V7, un variant impliqué dans la résistance à l'hormonothérapie
Formation of androgen receptor splicing variant 7 (AR-V7), a constitutively active form of AR, plays a key role in the resistance of prostate cancer to hormone therapy. However, the mechanisms that regulate AR-V7 generation are poorly understood. Here, we identified a new role for histone demethylase JMJD1A (Jumonji domain containing 1A) in the formation of AR-V7 in prostate cancer cells. We found that JMJD1A facilitated recruitment of a splicing factor, heterogeneous nuclear ribonucleoprotein F, for alternative splicing and generation of AR-V7. The findings suggest that targeting JMJD1A may provide new therapeutic opportunity for prostate cancer. Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy.