Histone Lactylation-Driven Ubiquitin-Specific Protease 34 Promotes Cisplatin Resistance in Hepatocellular Carcinoma.

Background: Ubiquitin-specific protease 34 (USP34) is a deubiquitinase that has been shown to play a critical role in the process of tumor drug-resistance. The objective of this study was to investigate the role of USP34 in cisplatin resistance in hepatocellular carcinoma (HCC).

Methods: Firstly, we analyzed the USP34 levels in cisplatin-sensitive and -resistant patients using The Cancer Genomic Atlas (TCGA) data from Gene Expression Profiling Interactive Analysis (GEPIA2). The cell viability and half-maximal inhibitory concentration (IC₅₀) were measured by Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis of HepG2 and HepG2/DDP cells was detected by annexin V-fluorescein isothiocyanate/propidium iodide (FITC/PI) double staining. The expression levels of USP34, multidrug resistance-associated protein 1 (MRP1), p-glycoprotein (p-gp), pan-lysine lactylation (Pan-Kla), histone H3 lysine 18 lactylation (H3K18la), lactate dehydrogenase A (LDHA) and lactate dehydrogenase B (LDHB) were measured by Western blot. HCC samples from the GEPIA2 database were used to determine the correlation between USP34 with LDHA and LDHB expression.

Results: USP34 was significantly upregulated in cisplatin-resistant HCC tissues and cells. Functional studies found that knockdown of USP34 inhibited HepG2 and HepG2/DDP cell proliferation and survival. Importantly, knockdown of USP34 enhanced cisplatin sensitivity in HepG2 and HepG2/DDP cells. Mechanistically, lactylation of histones promoted the expression level of USP34 in HepG2/DDP cells.

Conclusion: USP34 promotes the progression of HCC by regulating histone lactylation levels and cisplatin resistance in HCC.