Important Role of SUMOylation of Spliceosome Factors in Prostate Cancer Cells

Sentrin/SUMO
(small ubiquitin-like modifier)-specific proteases
(SENPs) have been implicated in the development of prostate cancer.
However, due to the low abundance of SUMO-modified proteins and high
activity of SENPs, the SUMO substrates affected by SENPs in prostate
cancer cells are largely unknown. Here, we identified SI2, a novel
cell-permeable SENP-specific inhibitor, by high-throughput screening.
Using SI2 as a way of inhibiting the activity of SENPs and the SUMO
stably transfected PC3 cells as a prostate cancer model, in combination
with the stable isotope labeling with amino acids (SILAC) quantitative
proteomic technique, we identified more than 900 putative target proteins
of SUMO, in which 231 proteins were further subjected to bioinformatic
analysis. In the highly enriched spliceosome pathway, we validated
that USP39, HSPA1A, and HSPA2 were novel target proteins of SUMO.
Furthermore, we demonstrated that K6, K16, K29, K51, and K73 were
the SUMOylation sites of USP39. Mutation of these SUMO modification
sites of USP39 further promoted the proliferation-enhancing effect
of USP39 on prostate cancer cells. This study provides the SUMOproteome
of PC3 cells and reveals that SUMOylation of spliceosome factors may
be implicated in the pathogenesis of prostate cancer. Optimization
of SI2 for isotype-specific SENP inhibitors warrants further investigation.