IADR Abstract Archives

Regulation of MASTL kinase in oral cancer resistance

Objectives: Oral cancer is the sixth most common cancer worldwide. In America, approximately 50,000 new oral cancer cases are diagnosed annually. To fight oral cancer, the University of Nebraska Medical Center (UNMC) College of Dentistry and many other dental practices now perform routine oral cancer screening tests to aid early detection. Available treatments for oral cancer typically include surgery, radiation and chemotherapy. Radiation and chemotherapeutics confer cancer cell cytotoxicity largely by disrupting DNA replication to induce DNA damage. Unfortunately, the prognosis of oral cancer, particularly HPV(-) cases, remains poor, calling for a better understanding of how cells respond to replication stress and DNA damage, and accordingly, developing more effective treatment options to overcome drug resistance.
Methods: We characterized a new role of microtubule-associated serine/threonine kinase-like (MASTL) in the replication stress and DNA damage responses. MASTL was frequently upregulated in HPV(-) oral cancer, in correlation with cancer progression, tumor recurrence and poor patient survival. MASTL promoted the recovery and resistance of oral cancer cells to drug-induced replication stress and DNA damage, which also upregulated MASTL expression, stressing the importance of MASTL regulation. Our proteomic analysis identified an E3 ubiquitin ligase as a novel associated protein of MASTL. Subsequently, the effect of this E3-ligase on MASTL expression was evaluated by immunoblotting and immunofluorescence. Lastly, the effect of this E3-ligase in the DNA damage response was examined by immunoblotting and flow cytometry.
Results: We characterized an E3-ligase that mediates MASTL degradation; its association with MASTL was disrupted by DNA damage or replication stress. Depletion of this E3-ligase impaired the DNA damage checkpoints, and facilitated cell recovery from drug treatments.
Conclusions: MASTL upregulation can result from its degradation modulation, which then promotes cell recovery and treatment resistance. MASTL and its regulators are potential prognostic markers and therapeutic targets to enhance the treatment outcome of oral cancer.
IADR/AADR/CADR General Session
2020 IADR/AADR/CADR General Session (Washington, D.C., USA)
Washington, D.C., USA
2020
2047
Pharmacology/Therapeutics/Toxicology
  • Li, Yanqiu  ( University of Nebraska Medical Center , Lincoln , Nebraska , United States )
  • Peng, Aimin  ( University of Nebraska Medical Center , Lincoln , Nebraska , United States )
  • NONE
    Poster Session
    Pathogenesis & Therapeutics