2. Academic Validation
  3. FAM83A Promotes the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma via PKM2-Mediated Aerobic Glycolysis

FAM83A Promotes the Progression and Metastasis of Head and Neck Squamous Cell Carcinoma via PKM2-Mediated Aerobic Glycolysis

  • FASEB J. 2025 Jul 31;39(14):e70796. doi: 10.1096/fj.202500989RR.
Yuyao Zhang 1 2 3,  Huan Ji 2 3 4,  Xiangyu Liu 5,  Rong Guo 6,  Zhenyuan Zhao 2 3 7,  Jing Wang 1 2 3,  Min Wu 2 3 8 9,  Yue Jiang 2 3 8 9,  Zhibai Zhao 1 2 3,  Yi Zhong 2 3 8 9,  Jinhua Yu 1 2 3
Affiliations

Affiliations

  • 1 Department of Endodontics, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
  • 2 State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases (Nanjing Medical University), Nanjing, China.
  • 3 Jiangsu Province Engineering Research Center of Stomatological Translational Medicine (Nanjing Medical University), Nanjing, China.
  • 4 Department of Geriatric Dentistry, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
  • 5 The First School of Clinical Medicine, Nanjing Medical University, Nanjing, China.
  • 6 Department of Stomatology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China.
  • 7 Department of Oral and Maxillofacial Surgery, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
  • 8 Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
  • 9 Department of Oral Pathology, The Affiliated Stomatological Hospital of Nanjing Medical University, Nanjing, China.
PMID: 40637278 DOI: 10.1096/fj.202500989RR
Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy that frequently results in mortality due to postoperative recurrence. In our previous study, we identified for the first time that the family with sequence similarity 83, member A (FAM83A), is overexpressed in HNSCC and associated with poor patient prognosis. However, its role in HNSCC metabolism remains unclear. M2-type Pyruvate Kinase 2 (PKM2) plays a critical role in glucose metabolic reprogramming in Cancer cells, but the regulatory network involving PKM2 and its interaction with FAM83A in HNSCC progression remains poorly understood. In this study, we investigate the relationship between FAM83A and PKM2 in HNSCC for the first time. The overexpression of PKM2 correlates with FAM83A upregulation in HNSCC clinical samples. Single-cell RNA Sequencing and RNA Sequencing analyses demonstrate that FAM83A enhances the glucose metabolism pathway in HNSCC. In vitro, FAM83A promotes glycolytic activity and accelerates lactate production in HNSCC. Inhibition of PKM2 reverses the increased lactate production, migration, invasion, and epithelial-mesenchymal transition (EMT) induced by FAM83A overexpression. Mechanistically, FAM83A promotes the transcriptional activation of PKM2 by activating the Wnt/β-catenin signaling pathway. Furthermore, the integration of FAM83A with Casein Kinase 1 alpha (CK1α) contributes to the activation of the Wnt/β-catenin signaling pathway. Finally, shikonin, a pharmacological inhibitor of PKM2, protects mice from HNSCC progression and metastasis induced by FAM83A in vivo. Our findings reveal that PKM2-mediated aerobic glycolysis induced by FAM83A promotes the progression and metastasis of HNSCC, presenting a promising therapeutic target for HNSCC patients.

Keywords

M2‐type pyruvate kinase; aerobic glycolysis; family with sequence similarity 83, member A protein; head and neck squamous cell carcinoma; oncogenesis.

Figures
Products