Entinostat overcomes cisplatin resistance in bladder cancer by promoting H3K18la-mediated DHRS2 expression and nuclear translocation to suppress the AKR1C3-androgen axis.

Epigenetic dysregulation is a significant factor contributing to cisplatin resistance in bladder cancer (BCa). Increasing studies indicated a synergistic effect of cisplatin and Entinostat, which is an FDA-approved histone deacetylases (HDAC) inhibitor, however, the underlying mechanisms of this effect remains unknown. Herein, the synergy of cisplatin and Entinostat was confirmed in BCa cells. Integrated RNA-seq and ATAC-seq analysis revealed that the combined regimen of cisplatin and Entinostat led to significant downregulation of platinum resistance and DNA damage repair-related pathways. We focused on the candidate gene dehydrogenase/reductase member 2 (DHRS2), and found that Entinostat counteracted cisplatin resistance via promoting histone H3K18 lactylation (H3K18la)-mediated DHRS2 upregulation and enhancing the nuclear translocation of DHRS2. DHRS2 downregulation promoted cisplatin resistance by upregulating aldo-keto reductase family 1 member C3 (AKR1C3), a key enzyme in androgen synthesis. Moreover, we validated a negative correlation between DHRS2 levels and AKR1C3 expression in clinical BCa samples. It was found that high DHRS2 and low AKR1C3 expression correlates with improved neoadjuvant chemotherapy (NAC) response. Furthermore, high DHRS2 predicts better survival specifically in male patients, indicating sex-specific androgen involvement. Overall, these findings elucidate the epigenetic mechanism underlying the cisplatin-sensitizing effect of Entinostat, and identifies the DHRS2-AKR1C3-androgen axis as a potential target, particularly for male patients.