Abstract

H2AFY binds ITM2A promoter and suppresses its transcription in HCC. • H2AFY promotes HCC progression via downregulating ITM2A and inhibiting autophagy. • H2AFY regulates autophagy-dependent ferroptosis through ITM2A. Background Hepatocellular carcinoma (HCC) is not only a widespread malignant tumor but also the third leading cause of cancer-related deaths. It has been reported that the expression level of H2AFY in HCC cells and tissues is relatively high and it contributes to the progression of HCC. However, its downstream targets remain unclear. Methods In this study, we used RT-qPCR and Western blot to evaluate the expression level of the target gene. To determine the growth of cells, we adopted CCK-8 assay, transwell assay and flow cytometry. The level of autophagy was detected by Western blot and immunofluorescence (IF). Ferroptosis was evaluated by DHE staining and ELISA assays. The growth of tumors in vivo was detected by xenograft experiment. Results This study reveals that H2AFY is enriched in the promoter region of ITM2A and inhibit its transcription. ITM2A is significantly correlated with the survival rate of liver cancer patients and is lowly expressed in tumor tissues and HCC cell lines. Knockdown of ITM2A in HCC cells promotes the proliferation, migration and invasion of HCC cells and inhibits cell apoptosis. In addition, knockdown of ITM2A inhibits autophagy, as evidenced by reduced expression of autophagy-related markers. Mechanistically, H2AFY inhibits autophagy and ferroptosis by suppressing ITM2A expression, thereby promoting HCC progression. Conclusion Overall, our findings demonstrate that targeting the H2AFY/ITM2A axis could serve as a therapeutic strategy for HCC. Download: Download high-res image (196KB) Download: Download full-size image