Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism

SIMPLE SUMMARY: Maintaining the energy stability is critical for cell surviving and adapting in a vagary environment. Glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) are two major energy production pathways in cells. Here we demonstrated that menin regulates the expression of OXPHOS and glycolytic genes, and this regulation can further be modified by a group of menin-associated proteins (MAPs) including KMT2A, MED12, WAPL, and GATA3. Downregulation of menin and MAP genes altered the proportion of glycolysis and OXPHOS for energy generation, and we found a counteracting function of menin and MAPs when the shRNA knockdown cells are exposed to metabolic stress. Menin and MAPs may serve as transcriptional sensors for balancing the preference between glycolysis and OXPHOS. This coordinated regulation is crucial for cell adaption to stressful microenvironments using different pathways for energy production. ABSTRACT: The interplay between glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) is central to maintain energy homeostasis. It remains to be determined whether there is a mechanism governing metabolic fluxes based on substrate availability in microenvironments. Here we show that menin is a key transcription factor regulating the expression of OXPHOS and glycolytic genes in cancer cells and primary tumors with poor prognosis. A group of menin-associated proteins (MAPs), including KMT2A, MED12, WAPL, and GATA3, is found to restrain menin’s full function in this transcription regulation. shRNA knockdowns of menin and MAPs result in reduced ATP production with proportional alterations of cellular energy generated through glycolysis and OXPHOS. When shRNA knockdown cells are exposed to metabolic stress, the dual functionality can clearly be distinguished among these metabolic regulators. A MAP can negatively counteract the regulatory mode of menin for OXPHOS while the same protein positively influences glycolysis. A close-proximity interaction between menin and MAPs allows transcriptional regulation for metabolic adjustment. This coordinate regulation by menin and MAPs is necessary for cells to rapidly adapt to fluctuating microenvironments and to maintain essential metabolic functions.