Abstract
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.
Highlights
Oral squamous cell carcinoma (OSCC) is one of the most prevalent head and neck SCCs (HNSCCs) worldwide. miRNAs are noncoding RNAs that play various important roles during pathogenesis by targeting transcripts and regulating their expression levels [1,2]. miR-31 has been shown to be an oncogenic miRNA upregulated in OSCC that modulates hypoxia, DNA repair, stemness, and various metabolic pathways [2,3,4,5,6,7,8]. miR-31 targets SIRT3 [7], ACOX1 [8], FIH [9,10], and SDHA [11] to disrupt metabolic homeostasis in malignancies
NUMB interacts with p53, MDM2, and PTEN to modulate their activity in the neoplastic process [14,16,19,20,21,22]. miR-31 targets NUMB to enhance oncogenicity in OSCC and colorectal carcinoma [23,24]
The present study provided novel clues demonstrating that NUMB binds MCT1/MCT4 to induce MCT1/MCT4 degradation, decrease oncogenicity, and increase glycolytic metabolism in OSCC cells
Summary
Oral squamous cell carcinoma (OSCC) is one of the most prevalent head and neck SCCs (HNSCCs) worldwide. miRNAs are noncoding RNAs that play various important roles during pathogenesis by targeting transcripts and regulating their expression levels [1,2]. miR-31 has been shown to be an oncogenic miRNA upregulated in OSCC that modulates hypoxia, DNA repair, stemness, and various metabolic pathways [2,3,4,5,6,7,8]. miR-31 targets SIRT3 [7], ACOX1 [8], FIH [9,10], and SDHA [11] to disrupt metabolic homeostasis in malignancies. MiR-31 has been shown to be an oncogenic miRNA upregulated in OSCC that modulates hypoxia, DNA repair, stemness, and various metabolic pathways [2,3,4,5,6,7,8]. NUMB is an adaptor protein that plays multifaceted roles in modulating cell functions, including neurogenesis, symmetric cell division in the stemness process, epithelialmesenchymal transition, and oncogenesis [12,13,14,15]. MiR-31 targets NUMB to enhance oncogenicity in OSCC and colorectal carcinoma [23,24]. The suppressor roles of NUMB against OSCC have been identified in previous studies [14,23], but its downstream effectors remain to be elucidated. Whether NUMB variants differentially modulate downstream effectors requires further investigation
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