HMGA2 alleviates ferroptosis by promoting GPX4 expression in pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is one of the most malignant tumor types characterized by high metastasis ability and low survival rate. As a chromatin-binding protein, HMGA2 is widely overexpressed and considered an oncogene with various undefined regulatory mechanisms. Herein, we demonstrated that HMGA2 is highly expressed in pancreatic cancer tissues and promotes tumor malignancy through cell proliferation, metastasis, and xenograft tumor growth in vivo. Moreover, HMGA2 enhanced the cellular redox status by inhibiting reactive oxygen species and promoting glutathione. Importantly, significantly ameliorated ferroptotic cell death was observed in cells overexpressing HMGA2. Conversely, HMGA2 deletion exacerbated ferroptosis. Mechanistically, HMGA2 activated GPX4 expression through regulation at transcription and translation levels. HMGA2 promoted cis-element modification in the promoter region of the GPX4 gene by enhancing enhancer activity through increased H3K4 methylation and H3K27 acetylation. Furthermore, HMGA2 stimulated GPX4 protein synthesis via the mTORC1-4EBP1 and -S6K signaling axis. The overexpression of HMGA2 alleviated the decreased GPX4 protein level resulting from the pharmacologic inhibition of mTORC1. Conversely, HMGA2 deletion more pronouncedly reduced the phosphorylation of 4EBP1 and S6K compared to the control. A strong positive correlation between HMGA2 and GPX4 expression was confirmed using immunohistochemistry staining. We also demonstrated that HMGA2 mitigated the sensitivity of cancer cells to combination treatment with a ferroptosis inducer and mTORC1 inhibition or gemcitabine. In summary, our results revealed a regulatory mechanism by which HMGA2 coordinates GPX4 expression and underscores the potential value of targeting HMGA2 in cancer treatment.