ZBTB20 promotes ferroptosis through inhibiting TMEM109 expression in glioblastoma cells

Ferroptosis is an iron‑dependent type of regulated cell death which is dysregulated in several tumors, including glioblastoma (GBM). Zinc finger and BTB domain‑containing protein 20 (<i>ZBTB20</i>), a transcription repressor, is expressed at low levels in GBM and suppresses GBM cell proliferation through the ERK signaling pathway. However, the effect of <i>ZBTB20</i> on ferroptosis has not been explored. The present study aimed to explore the role of ZBTB20 in ferroptosis of glioma cells and its underlying mechanism. The present study demonstrated that both <i>ZBTB20</i> expression and ferroptosis levels in GBM cells were lower than that in normal glial cells. Gain‑ and loss‑of‑function experiments revealed that <i>ZBTB20</i> overexpression promoted ferroptosis and <i>ZBTB20</i> knockdown inhibited ferroptosis in GBM cells. Moreover, the results demonstrated that <i>ZBTB20</i> transcriptionally repressed the expression of transmembrane protein 109 (<i>TMEM109</i>) in GBM cells, assessed using dual‑luciferase reporter and chromatin immunoprecipitation assays. TMEM109 is mainly localized on the endoplasmic reticulum (ER) membrane of cells and regulates calcium leakage at the ER or sarcoplasmic reticulum. The present study revealed that <i>TMEM109</i> overexpression inhibited ferroptosis and <i>TMEM109</i> knockdown promoted ferroptosis in GBM cells. Using co‑transfection experiments, it was further revealed that the promotive effect of <i>ZBTB20</i> can reverse the inhibitory effect of TMEM109 on ferroptosis. In conclusion, the findings indicated that <i>ZBTB20</i> promotes ferroptosis in GBM cells through transcriptionally repressing the expression of <i>TMEM109</i>.