Dissecting the post-translational regulation and oncological activity of the protease Taspase1 in head and neck cancer

• Applicant: Dr. Jan Hagemann
• Subject Area: Otolaryngology, Phoniatrics and Audiology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 426607720

Key to the long-term improvement of cancer treatments is a molecular understanding of mechanisms contributing to tumorigenesis. Proteases are important players for cancer and thus, clinically accepted targets for anti-cancer therapies. The unique protease Threonine Aspartase-1 (Taspase1) contributes not only to the development of leukemia, but also to solid tumors, such as head and neck cancer. Thus, head and neck cancer provides a clinical relevant model system for the elucidation of proteolytic Taspase1 networks. Based on our current knowledge, the identification of additional novel cellular mechanisms regulating the protease’s (patho)biological activity is not only key to dissect Taspase1’s signaling pathways, but also for the evaluation of its relevance in health and disease.Others and we showed that post-translational modifications, such as acetylation, impact key cancer regulators, but are unknown for proteases. Interestingly, our preliminary work provides comprehensive experimental evidence that: 1. Taspase1 is post-translationally modified by acetylation within its α and β subunit; 2. acetylated lysine residues can be identified by mass spectrometry; 3. GCN5 and HDAC1 interact with Taspase1 and dynamically affect its acetylation status; and 4. Taspase1 deacetylation prevents cleavage of its native substrate USF2 . Hence, we hypothesize that Taspase1's (patho)biological activity may be (co)regulated by dynamic acetylation. Consequently, the scientific objectives of the project are:I. Identification of histone acetyltransferases and histone deacetylases mediating Taspase1’s dynamic acetylation.II. Mapping of Taspase1 residues critical for acetylation.III. Characterizing the relevance of acetylation for Taspase1’s catalytic activity and substrate specificity.IV. Impact of Taspase1 acetylation on its degradome.Collectively, the proposed project aims to understand the impact of dynamic acetylation on Taspase1’s (patho)biology, and its relevance for tumor development and progression in head and neck tumors. The generated knowledge will not only define a regulatory mechanism, so far unknown for proteases, but may also provide a framework for novel therapeutic intervention strategies.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Roland H. Stauber