Panoply™ Human HDAC8 Knockdown Stable Cell Line

Nephrotoxicity is a major side effect of platinum-based anticancer drugs, and currently, there is no effective treatment. Here, researchers demonstrate that targeting histone deacetylase 8 (HDAC8) may be a potential strategy for treating cisplatin-induced acute kidney injury (AKI). In a cisplatin-induced AKI mouse model, administration of the HDAC8 selective inhibitor PCI-34051 significantly improved renal function and reduced renal tubular damage and apoptosis. Pharmacological inhibition of HDAC8 also decreased the cleavage of caspase-3 and PARP1, attenuated Bax expression, and maintained Bcl-2 levels in the damaged kidneys. In cultured mouse renal tubular epithelial cells (mRTECs) exposed to cisplatin, treatment with PCI-34051 or transfection with HDAC8 siRNA reduced the number of apoptotic cells and decreased the expression of cleaved caspase-3 and PARP1; conversely, overexpression of HDAC8 exacerbated these changes. Furthermore, PCI-34051 reduced the expression levels of p53, p21, p-CDK2, and γ-H2AX in the damaged kidneys while maintaining MRE11 expression. Similarly, pharmacological and genetic inhibition of HDAC8 reduced γ-H2AX expression and enhanced MRE11 expression; conversely, in mRTECs exposed to cisplatin, overexpression of HDAC8 exacerbated these changes. These results suggest that HDAC8 inhibition can alleviate cisplatin-induced AKI through mechanisms involving reduced DNA damage and enhanced DNA repair.

To confirm the role of HDAC8 in cisplatin-induced renal epithelial cell apoptosis, researchers used mRTEC cells with HDAC8 knockdown and HDAC8 overexpression. Compared to control cells, HDAC8 knockdown cells showed reduced apoptosis and lower expression levels of cleaved PARP1 and cleaved caspase-3 after exposure to cisplatin (Figure 1A-C). Furthermore, HDAC8 knockdown increased histone acetylation levels after exposure to cisplatin (Figure 1A, D). The survival rate of HDAC8 knockdown cells after exposure to cisplatin was higher than that of control cells (Figure 1E). Conversely, HDAC8 overexpression decreased histone acetylation levels (Figure 1I) and exacerbated cisplatin-induced apoptosis, as evidenced by increased levels of cleaved PARP1 and cleaved caspase-3 and decreased cell viability (Figure 1F-H, J). These results further support the idea that HDAC8 is involved in regulating renal epithelial cell apoptosis.

Figure 1. HDAC8 exacerbates histone deacetylation and promotes cisplatin-induced apoptosis in renal tubular epithelial cells. (Wang Y, et al., 2024)