KLF4 Regulates Metabolic Homeostasis in Response to Stress

Cancerous cells are detrimental to the human body and can be incredibly resilient against treatments because of the complexities of molecular carcinogenic pathways. In particular, cancer cells are able to sustain increased growth under metabolic stress due to phenomena like the Warburg effect. Krüppel-like factor 4 (KLF4), a context-dependent transcription factor that can act as both a tumor suppressor and an oncogene, is involved in many molecular pathways that respond to low glucose and increased reactive oxygen species (ROS), raising the question of its role in metabolic stress as a result of increased proliferation of tumor cells. In this study, metabolic assays were performed, showing enhanced efficiency of energy production in cells expressing KLF4. Western blotting showed that KLF4 increases the expression of essential glycolytic proteins. Furthermore, we used immunostaining to show that KLF4 increases the localization of glucose transporter 1 (GLUT1) to the cellular membrane. 2',7'-Dichlorodihydrofluorescein diacetate (H₂DCF-DA) was used to analyze the production of ROS, and we found that KLF4 reduces stress-induced ROS within cells. Finally, we demonstrated increased autophagic death in KLF4-expressing cells in response to glucose starvation. Collectively, these results relate KLF4 to non-Warburg metabolic behaviors that support its role as a tumor suppressor and could make KLF4 a target for new cancer treatments.