<i>miR-31</i>-<i>NUMB</i> Cascade Modulates Monocarboxylate Transporters to Increase Oncogenicity and Lactate Production of Oral Carcinoma Cells
Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. <i>miR-31</i> is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the <i>miR-31</i>-<i>NUMB</i&g...
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| Main Authors: | , , , , , , |
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| Format: | article |
| Language: | EN |
| Published: |
MDPI AG
2021
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| Subjects: | |
| Online Access: | https://doaj.org/article/d858cb94452b47c89ce80db39bb95cb9 |
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| Summary: | Oral squamous cell carcinoma (OSCC) is among the leading causes of cancer-associated death worldwide. <i>miR-31</i> is an oncogenic miRNA in OSCC. NUMB is an adaptor protein capable of suppressing malignant transformation. Disruption of the <i>miR-31</i>-<i>NUMB</i> 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 <i>MCT1</i> and <i>MCT4</i> has been shown to be a prognostic factor of OSCC. Here, we reported that <i>miR-31-NUMB</i> can modulate glycolysis in OSCC. Using the CRISPR/Cas9 gene editing strategy, we identified increases in oncogenic phenotypes, <i>MCT1</i> and <i>MCT4</i> expression, lactate production, and glycolytic respiration in <i>NUMB</i>-deleted OSCC subclones. Transfection of the <i>Numb1</i> or <i>Numb4</i> isoform reversed the oncogenic induction elicited by <i>NUMB</i> 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 <i>miR-31</i> deletion and <i>NUMB</i> deletion were partially rescued by <i>MCT1</i>/<i>MCT4</i> expression or knockdown. This study demonstrated that NUMB is a novel binding partner of MCT1 and MCT4 and that the <i>miR-31</i>-<i>NUMB</i>-<i>MCT1/MCT4</i> regulatory cascade is present in oral carcinoma. |
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