Hepatocellular Carcinoma Cells in Humans Exhibit Resistance to Suberoylanilide Hydroxamic Acid (<scp>SAHA</scp>) Owing to the Diminished Level of Hsa‐<scp>miR</scp>‐125a‐5p

Hepatocellular carcinoma (HCC) presents an escalating public health challenge globally. However, drug resistance has emerged as a major impediment to successful HCC treatment, limiting the efficacy of curative interventions. Despite numerous investigations into the diverse impacts of hsa-miR-125a-5p on tumor growth across different cancer types, its specific involvement in chemotherapy resistance in HCC remains elusive. Our study aims to explore the potential involvement of hsa-miR-125a-5p in HCC drug resistance using HA22T cell lines: HA22T and HA22T-HDACi-resistance cells. The HA22T-HDACi-resistance cell line is an established liver cancer cell line that is resistant to histone deacetylase inhibitors (HDACi), apicidin, and suberoylanilide hydroxamic acid (SAHA). Utilizing qPCR, the levels of hsa-miR-125a-5p showed a notable decrease in the HA22T-HDACi-resistance cell line compared with HA22T cells. Subsequently, we examined the influence of hsa-miR-125a-5p expression on cell death in both cell lines. The findings demonstrated that alterations in hsa-miR-125a-5p levels directly impacted apoptosis in both HA22T and HA22T-HDACi-resistance cell lines with SAHA treatment. Afterwards, we recognized TRAF6 as a target gene of hsa-miR-125a-5p, shedding light on its potential role in modulating apoptosis via targeting TRAF6 in HCC. These findings underscore the potential significance of hsa-miR-125a-5p in overcoming drug resistance in HCC, offering insights into its dual role in apoptosis modulation and TRAF6 targeting. The study suggests that hsa-miR-125a-5p may inhibit expression of TRAF6 in HCC, presenting a promising avenue for gene therapy in HCC with HDACi resistance.