FOXM1 augments sorafenib resistance and promotes progression of hepatocellular carcinoma by epigenetically activating KIF23 expression

by Selleckchem | Sep 19 2023

Sorafenib has been used to enhance the survival outcome of hepatocellular carcinoma (HCC) patients. But, occurrence resistance to sorafenib subtracts from its therapeutic benefits. Herein, we identified that FOXM1 was markedly upregulated in both tumor samples and sorafenib-resistant HCC tissues. We also demonstrated that patients with decreased FOXM1 expression had longer overall survival (OS) and progression-free survival (PFS) in the cohort of sorafenib-treated patients. For HCC cells resistant to sorafenib, the IC50 value of sorafenib and the expression of FOXM1 were increased. In addition, Downregulation of FOXM1 expression alleviated the occurrence of resistance to sorafenib and reduced the proliferative potential and viability of HCC cells. Mechanically, the suppression of the FOXM1 gene resulted in the downregulation of KIF23 levels. Moreover, downregulation of FOXM1 expression reduced the levels of RNA polymerase II (RNA pol II) and histone H3 lysine 27 acetylation (H3K27ac) on the KIF23 promoter, further epigenetically silencing the production of KIF23. More intriguingly, our results similarly revealed that FDI-6, a specific inhibitor of FOXM1, suppressed the proliferation of HCC cells resistant to sorafenib, as well as upregulation of FOXM1 or KIF23 abolished this effect. In addition, we found that FDI-6 combined with sorafenib significantly improved the therapeutic effect of sorafenib. Collectively, the present results revealed that FOXM augments sorafenib resistance and enhances HCC progression by upregulating KIF23 expression via an epigenetic mechanism, and targeting FOXM1 can be an effective treatment for HCC.

Comments:

The passage you provided discusses the role of the protein FOXM1 in hepatocellular carcinoma (HCC) and its relationship with sorafenib resistance. Here's a breakdown of the key findings:

1. FOXM1 Upregulation: The researchers observed that FOXM1 expression was significantly increased in both tumor samples and sorafenib-resistant HCC tissues. This suggests a potential association between FOXM1 and sorafenib resistance.

2. FOXM1 and Patient Survival: The study found that patients with lower FOXM1 expression levels had longer overall survival (OS) and progression-free survival (PFS) when treated with sorafenib. This indicates that decreased FOXM1 expression may be a favorable prognostic factor for HCC patients receiving sorafenib treatment.

3. Sorafenib Resistance and FOXM1: HCC cells resistant to sorafenib exhibited higher IC50 values (indicating reduced sensitivity to the drug) and increased FOXM1 expression levels. This suggests that FOXM1 may contribute to the development of resistance to sorafenib in HCC cells.

4. FOXM1 Suppression and HCC Cell Characteristics: When FOXM1 expression was downregulated, the occurrence of sorafenib resistance was alleviated, and the proliferative potential and viability of HCC cells were reduced. This suggests that targeting FOXM1 may help overcome sorafenib resistance and inhibit the growth of HCC cells.

5. FOXM1 and KIF23: The researchers found that suppression of the FOXM1 gene led to the downregulation of KIF23 levels. Furthermore, downregulation of FOXM1 expression reduced the levels of RNA polymerase II (RNA pol II) and histone H3 lysine 27 acetylation (H3K27ac) on the KIF23 promoter, which epigenetically silenced KIF23 production. This indicates that FOXM1 may regulate the expression of KIF23 through an epigenetic mechanism.

6. Inhibition of FOXM1: FDI-6, a specific inhibitor of FOXM1, was found to suppress the proliferation of sorafenib-resistant HCC cells. However, when FOXM1 or KIF23 expression was upregulated, this effect was abolished. This suggests that targeting FOXM1 using FDI-6 may be a potential therapeutic approach for overcoming sorafenib resistance in HCC.

7. Combination Therapy: Additionally, the researchers discovered that combining FDI-6 with sorafenib significantly improved the therapeutic effect of sorafenib. This suggests that the combination of FOXM1 inhibition and sorafenib treatment may have a synergistic effect in treating HCC.

In summary, the study identifies FOXM1 as a key player in sorafenib resistance and HCC progression. Upregulation of FOXM1 leads to increased expression of KIF23 through an epigenetic mechanism, contributing to sorafenib resistance. Targeting FOXM1, either with a specific inhibitor like FDI-6 or in combination with sorafenib, could be a promising therapeutic strategy for HCC treatment.