Dissecting the post-translational regulation and oncological activity of the protease Taspase1 in head and neck cancer
Final Report Abstract
Post-translational acetylation of non-histone proteins is one of the most important molecular switches regulating multiple cellular pathways. Remarkably, proteases are clearly underrepresented in the predicted human acetylome. Threonine Aspartase1 (Taspase1) is a protease with pathobiological relevance and is regulated by yet unresolved mechanisms. Previous work has shown increased Taspase1 expression in head and neck tumors, so that Taspase1 has become the focus of research as a promising new biomarker. To close the existing knowledge gaps, our project followed a tiered experimental workflow consisting of cell-based assays, state-of-the-art proteomic analyses (MS, TAILS) and analysis of clinical patient data. In summary, our work has unraveled several new features of Taspase1 biology: Several novel characteristics of Taspase1 biology have emerged from this study: (i) Taspase1 is modified by different histone acetyltransferases (e.g., GCN5) in a subunitand concentration-dependent manner; (ii) deacetylation of the protease is specifically catalyzed by the deacetylase HDAC1 exhibiting an N-terminal Taspase1 interaction domain, but not by HDAC2; (iii) the acetylation status of the lysine residue K258 is critical for overall Taspase1 acetylation, as well as for its trans cleavage activity, assuming a role as “master acetylation switch”; (iv) deacetylation of Taspase1 by HDAC1 abolishes its proteolytic cleavage activity shown by reduced cleavage of the natural Taspase1 substrates MLL, TFIIA and USF2; (v) generation of acetylation mutants and subsequent TAILS analysis of the degradome suggest previously unknown substrates of Taspase1 whose cleavage can be regulated in an acetylation-dependent manner. Furthermore, head and neck tumor patients with HDAC1high/ Taspase1high expressing tumors exhibit poor overall survival giving evidence that this molecular switch is indeed of clinical relevance. In conclusion, we uncovered a novel molecular mechanism how Taspase1´s degradome can be fine-tuned by dynamic de-/acetylation. Thus, these results can help improving the general understanding of signaling pathways in solid cancers
Publications
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IsoMAG—An Automated System for the Immunomagnetic Isolation of Squamous Cell Carcinoma-Derived Circulating Tumor Cells. Diagnostics, 11(11), 2040.
Gribko, Alena; Stiefel, Janis; Liebetanz, Lana; Nagel, Sophie Madeleine; Künzel, Julian; Wandrey, Madita; Hagemann, Jan; Stauber, Roland H.; Freese, Christian & Gül, Désirée
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Profiling Cisplatin Resistance in Head and Neck Cancer: A Critical Role of the VRAC Ion Channel for Chemoresistance. Cancers, 13(19), 4831.
Siemer, Svenja; Fauth, Torsten; Scholz, Paul; Al-Zamel, Yara; Khamis, Aya; Gül, Désirée; Freudelsperger, Laura; Wollenberg, Barbara; Becker, Sven; Stauber, Roland H. & Hagemann, Jan
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Cloning Strategy for HDAC1/HDAC2 Hybrid Protein Expression in Mammalian Cells. Methods in Molecular Biology, 401-409. Springer US.
Gül, Désirée; Olf, Sandra; Hagemann, Jan; Stauber, Roland H. & Krämer, Oliver H.
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Impact of Secretion-Active Osteoblast-Specific Factor 2 in Promoting Progression and Metastasis of Head and Neck Cancer. Cancers, 14(9), 2337.
Gül, Désirée; Schweitzer, Andrea; Khamis, Aya; Knauer, Shirley K.; Ding, Guo-Bin; Freudelsperger, Laura; Karampinis, Ioannis; Strieth, Sebastian; Hagemann, Jan & Stauber, Roland H.
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The Vitamin D Receptor–BIM Axis Overcomes Cisplatin Resistance in Head and Neck Cancer. Cancers, 14(20), 5131.
Khamis, Aya; Gül, Désirée; Wandrey, Madita; Lu, Qiang; Knauer, Shirley K.; Reinhardt, Christoph; Strieth, Sebastian; Hagemann, Jan & Stauber, Roland H.
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Exploiting Vitamin D Receptor and Its Ligands to Target Squamous Cell Carcinomas of the Head and Neck. International Journal of Molecular Sciences, 24(5), 4675.
Koll, Laura; Gül, Désirée; Elnouaem, Manal I.; Raslan, Hanaa; Ramadan, Omneya R.; Knauer, Shirley K.; Strieth, Sebastian; Hagemann, Jan; Stauber, Roland H. & Khamis, Aya
