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Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide.  miR-31  is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the  miR-31 - NUMB  regulatory axis has been demonstrated in malignancies. Mitochondrial dysfunction and adaptation to glycolytic respiration are frequent events in malignancies. Monocarboxylate transporters (MCTs) function to facilitate lactate flux in highly glycolytic cells. Upregulation of  MCT1  and  MCT4  has been shown to be a prognostic factor of OSCC. Here, we reported that  miR-31-NUMB  can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes,  MCT1  and  MCT4  expression, lactate production, and glycolytic respiration in  NUMB -deleted OSCC subclones. Transfection of the  Numb1  or  Numb4  isoform reversed the oncogenic induction elicited by  NUMB  deletion. This study also showed, for the first time, that NUMB4 binds MCT1 and MCT4 and that this binding increases their ubiquitination, which may decrease their abundance in cell lysates. The disruptions in oncogenicity and metabolism associated with  miR-31  deletion and  NUMB  deletion were partially rescued by  MCT1 / MCT4  expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the  miR-31 - NUMB - MCT1/MCT4  regulatory cascade is present in oral carcinoma.

miR-31-NUMB Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells