Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic
options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of
PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of
YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown
via siRNA resulted in reduced PM cell growth, which significantly correlated with
wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and
its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell
lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse
xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced
sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic
interactions with cisplatin which was linked to significantly increased cellular platinum
uptake in all investigated cell models. Importantly, in a mouse model, the combination
of cisplatin and entinostat also resulted in stronger growth inhibition than each
treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates
that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and
radiation sensitivity.
