PKM2 is the Metabolic Checkpoint for Stemness Features in Head and Neck Cancer

Owing to their self-renewal, differentiation capabilities, and increased chemoresistance, cancer stem cells (CSCs) are associated with poor prognosis and an elevated chance of relapse and metastasis. CSCs survive under therapy-imposed pressure and aggravate tumor malignancy through metabolic reprogramming, leading to treatment failure. The RNA level of pyruvate kinase isoenzyme M2 (PKM2) is increased in head and neck cancer (HNC) tissues and is linked to poor prognosis, whereas PKM2 deletion was found to accelerate tumorigenesis and tumor growth in vivo, leading to a paradox between PKM2 expression and tumorigenesis. To date, the role of PKM2 inhibition in HNC progression remains unclear. In the present study, we found that low PKM2 protein expression was significantly associated with later stages and higher grades of cancer in HNC tissues. Following PKM2 silencing, HNC cells exhibited significantly increased ATP levels, decreased lactate production, and upregulated mitochondrial respiratory activity. In addition, PKM2 knockdown promoted clonogenicity, motility, nuclear-activated β-catenin, CSC formation, and in vivo tumorigenicity in HNC cells. PKM2 inhibition further augmented stemness and resistance to chemotherapeutic drugs in HNC CSCs. Whole-genome transcriptome analysis of PKM2-knockdown CSCs revealed upregulation of differentially expressed genes (DEGs) in the Wnt signaling pathway. The present study concluded that decreased PKM2 is associated with aggressive clinicopathological features. PKM2 inhibition-promoted stemness may be mediated by increased nuclear β-catenin localization, which potentially contributes to tumorigenesis and disease progression in HNC. Our findings suggest that PKM2 modulates HNC stemness by linking metabolic rewiring with oncogenic signaling, highlighting its potential as a molecular target for adjuvant therapy in patients with HNC.