MYBL2 Knockdown Enhances Ferroptosis and Bortezomib Sensitivity by Transcriptionally Regulating CDKN3 and Inactivating PI3K/Akt Signaling in Multiple Myeloma

ABSTRACT MYBL2 is an oncogene that has been found to be upregulated in diverse cancers. However, the role of MYBL2 in multiple myeloma (MM) remains unclear. Here we used bioinformatic analysis to identify the differentially expressed genes in MM. In this study, western blot was conducted to detect protein levels. Ferroptosis was evaluated by detecting reactive oxygen species (ROS), ferrous iron (Fe 2+ ), lipid peroxidation, and glutathione (GSH) levels. Cell viability and apoptosis were detected by the cell counting kit‐8 assay and flow cytometry, respectively. Luciferase reporter assay was performed to confirm the binding between MYBL2 and CDKN3. We found that MYBL2 upregulation was observed in MM. Further in vitro studies showed that knockdown of MYBL2 promoted ferroptosis with increased ROS production, Fe 2+ content, lipid peroxidation level, and reduced GSH content. MYBL2 knockdown also enhanced the bortezomib (BTZ) sensitivity of MM cells. In addition, CDKN3 was identified as a downstream target of MYBL2. CDKN3 overexpression prevented the effects of si‐MYBL2 on ferroptosis and BTZ sensitivity in MM cells by interacting with the PI3K/Akt signaling pathway. In conclusion, knockdown of MYBL2 promoted ferroptosis and enhanced the BTZ sensitivity of MM cells through transcriptional regulation of CDKN3 and inactivation of the PI3K/Akt signaling pathway.