Menin and Menin-Associated Proteins Coregulate Cancer Energy Metabolism

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.

Menin–MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers

“…In order to address this question, pharmacological formulations, pharmacokinetic studies, and long-term toxicity in other species should be investigated in the following studies. More intriguingly, the type of thiophenpyrimidine inhibitors was also revealed to be effective in inhibiting the proliferation of solid tumors, including prostate cancer [ 5 , 29 ], liver cancer [ 6 ], breast cancer [ 27 ], lung cancer [ 23 ], and osteosarcoma [ 50 ]. However, the molecular mechanism of these menin/MLL1 small molecules inhibiting the proliferation of solid tumor cells is not clear, and it can be roughly understood that they have a synergistic effect with tumor chemotherapy drugs and may participate in the signaling pathway of chemotherapy drugs to inhibit tumors, which comprises speculation and needs to be further proven.…”

“…However, compared to OXPHOS, this transient inhibition had less effect on glycolysis and was quickly recovered. Thus, the MI-503 treatment significantly reduced the amount of ATP produced by OXPHOS, but the existing glycolytic enzymes continued to function and were able to compensate for the energy loss [ 27 ].…”

BCAT1 inhibition affects CD8+T cell activation, exhaustion, and tumoral immunity by altering iron homeostasis

“…We have speculated that the appearance of those CD8 + T cells is the result of epigenetic changes driven by certain histone modifications such as downregulation of the histone acetyltransferase Kat2b (which is expected to increase ribosome biogenesis) and downregulation of histone methyltransferase Kmt2a (which is expected to enhance OXPHOS) (Fig. 5E) (51,52). As an immuno-tuning tool, BCAT1i can be used either in a CAR-T cell setting, prior to the cell transfer to prevent and/or suppress the rise of an exhaustive phenotype in the CAR-T cells, or in combination with an ICI, to increase the cytotoxicity of reinvigorated CD8 + T cells in the TME.…”

Recent Progress of Small Molecule Menin–MLL Interaction Inhibitors as Therapeutic Agents for Acute Leukemia

“…Menin protein is a cofactor of leukemia caused by MLL fusion proteins. Numerous studies have indicated that the interaction between menin and the MLL fusion proteins is involved in the development of leukemia induced by MLL fusion proteins. − As a tumor suppressor encoded by multiple endocrine tumor type 1 gene (MEN1), menin consists of 610 residues and is recognized as a scaffold protein involved in the protein–protein interaction network. − The crystal structure of menin is like a curved left-hand, in which the N-terminal domain is depicted as a thumb, the middle region adopts the shape of the palm, and the C-terminus resembles curved fingers (Figure A and B) . Notably, the palm forms a deep pocket that is occupied by the conserved MLL MBM (MLL menin-binding motif), which is the N-terminus motif of MLL consisting of residues 6–25.…”