NaB-induced inhibition of HDAC4 and TUG1: a novel strategy for reversing oxaliplatin resistance in colorectal cancer

BACKGROUND: Oxaliplatin (OXA) resistance affects the efficacy of colorectal cancer (CRC) treatment. METHODS: Gene expression profiles of OXA-resistant and OXA-sensitive cells were compared to identify differentially expressed non-coding RNAs. A dual-luciferase assay was used to research the targeting relationship and binding region of TUG1 and miR-449a. SiRNA interference was used to construct cell models of OXA-resistant cells with low expression of TUG1 and OXA-sensitive cells with high expression of HDAC, as well as animal models based on these two types of cells. Then, cellular function was assessed. Histopathologic conditions were assessed by immunohistochemistry. RESULTS: TUG1, miR-449a and Histone Deacetylase 4 (HDAC4) were all upregulated in OXA-resistant cells, and the increase of HDAC4 was accompanied by a decrease in acetylation level. TUG1 binds to miR-449a, and TUG1 was located in the cytoplasm of OXA-resistant cells. Downregulated expression of TUG1 could inhibit proliferation and induce apoptosis in OXA-resistant cells and reverse OXA resistance. Downregulated expression of HDAC4 could reduce the expression of TUG1, and inhibit proliferation and induce apoptosis of OXA-resistant cells. Treatment with 2 mmol/L sodium butyrate (NaB), a histone deacetylase inhibitor, markedly suppressed tumor cell growth through regulation of TUG1 compared with 0.01 mmol/L NaB. The OXA-resistant tumor-bearing mouse experiment further confirmed the inhibitory effect of NaB on tumor. CONCLUSION: High-dose NaB can inhibit the expression of HDAC4, and then reduce the expression of TUG1 through acetylation modification, thereby inhibiting the development of CRC and reversing OXA resistance in CRC.