Ubiquitin-dependent regulation of the DNA damage-induced apoptosis and relevance for the chemoresistance of refractory CLL

• Applicants: Professor Dr. Thorsten Hoppe; Professor Dr. Hamid Kashkar
• Subject Area: Hematology, Oncology ; Immunology
• Term: from 2013 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 226262100

Final Report Abstract

Biochemical analyses have characterized the BH3-only protein family member NOXA as a “sensitizer” with weak pro-apoptotic activity. Investigations into cancer cell responses to chemotherapeutic agents have however identified NOXA as a pivotal factor mediating the cytotoxic effect of a plethora of anticancer treatments independent of its own pro-apoptotic activity. Accumulating evidence now suggests that tumor cells exert a number of strategies to counteract NOXA function by exploiting diverse cellular regulatory circuits that normally govern NOXA expression during cellular stress responses. Through its distinctive antagonistic specificity for MCL1, NOXA represents a critical factor in the regulation of cell death. The high prevalence of dysregulation of NOXA in cancer, together with observations that reactivation of NOXA under diverse settings restores cytotoxic activity of a number of chemotherapeutics, strongly supports the design and evaluation of therapeutic protocols aiming to restore NOXA function or mimic NOXA action. Knowledge of how NOXA provokes a potent anticancer effect and in combination with which chemotherapeutic agents will greatly advance development of cancer therapeutic regimens. Our data identified another mode in controlling the cytosolic pool of NOXA which can be exploited for the design of novel therapeutic protocols for cancer.

Publications

• Ubiquitin C-terminal hydrolase-L1 potentiates cancer chemosensitivity by stabilizing NOXA. Cell Rep. 2013 Mar 28;3(3):881-91
  Brinkmann K, Zigrino P, Witt A, Schell M, Ackermann L, Broxtermann P, Schüll S, Andree M, Coutelle O, Yazdanpanah B, Seeger JM, Klubertz D, Drebber U, Hacker UT, Krönke M, Mauch C, Hoppe T, Kashkar H
  (See online at https://doi.org/10.1016/j.celrep.2013.02.014)
• Noxa and cancer therapy: Tuning up the mitochondrial death machinery in response to chemotherapy. Mol Cell Oncol. 2014 Jul 28;1(1):e29906
  Albert MC, Brinkmann K, Kashkar H
  (See online at https://doi.org/10.4161/mco.29906)
• Targeting the mitochondrial apoptotic pathway: a preferred approach in hematologic malignancies? Cell Death Dis. 2014 Mar 6;5(3):e1098
  Brinkmann K, Kashkar H
  (See online at https://doi.org/10.1038/cddis.2014.61)
• Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia. 2015 Apr;29(4):981-4
  Huelsemann MF, Patz M, Beckmann L, Brinkmann K, Otto T, Fandrey J, Becker HJ, Theurich S, von Bergwelt-Baildon M, Pallasch CP, Zahedi RP, Kashkar H, Reinhardt HC, Hallek M, Wendtner CM, Frenzel LP
  (See online at https://doi.org/10.1038/leu.2014.320)
• Regulation of the DNA Damage Response by Ubiquitin Conjugation. Front. Genet. 2015 Mar 10;6:98
  Brinkmann K, Schell M, Hoppe T, Kashkar H
  (See online at https://doi.org/10.3389/fgene.2015.00098)
• B-cellspecific conditional expression of Myd88p.L252P leads to the development of diffuse large B- cell lymphoma in mice. Blood. 2016 Jun 2;127(22):2732-41
  Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, Fritz C, Vlantis K, Bezhanova S, Scheel AH, Wolz OO, Reimann M, Möller P, López C, Schlesner M, Lohneis P, Weber AN, Trümper L; German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium, Staudt LM, Ortmann M, Pasparakis M, Siebert R, Schmitt CA, Klatt AR, Wunderlich FT, Schäfer SC, Persigehl T, Montesinos-Rongen M, Odenthal M, Büttner R, Frenzel LP, Kashkar H, Reinhardt HC
  (See online at https://doi.org/10.1182/blood-2015-11-684183)
• Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression. Nat Commun. 2016 Feb 4;7:10612. Erratum in: Nat Commun. 2016 May 17;7:11593
  Franz A, Pirson PA, Pilger D, Halder S, Achuthankutty D, Kashkar H, Ramadan K, Hoppe T
  (See online at https://doi.org/10.1038/ncomms10612)
• E4 ligasespecific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. Nat Struct Mol Biol. 2016 Nov;23(11):995-1002
  Ackermann L, Schell M, Pokrzywa W, Kevei É, Gartner A, Schumacher B, Hoppe T
  (See online at https://doi.org/10.1038/nsmb.3296)
• Ring of Change: CDC48/p97 Drives Protein Dynamics at Chromatin. Front Genet. 2016 May 3;7:73
  Franz A, Ackermann L, Hoppe T
  (See online at https://doi.org/10.3389/fgene.2016.00073)
• A combination of lowdose bevacizumab and imatinib enhances vascular normalisation without inducing extracellular matrix deposition. Br J Cancer. 2017 Feb 28;116(5):600-608
  Schiffmann LM, Brunold M, Liwschitz M, Goede V, Loges S, Wroblewski M, Quaas A, Alakus H, Stippel D, Bruns CJ, Hallek M, Kashkar H, Hacker UT, Coutelle O
  (See online at https://doi.org/10.1038/bjc.2017.13)
• Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature. 2019 Nov;575(7784):683-687
  Fritsch M, Günther SD, Schwarzer R, Albert MC, Schorn F, Werthenbach JP, Schiffmann LM, Stair N, Stocks H, Seeger JM, Lamkanfi M, Krönke M, Pasparakis M, Kashkar H
  (See online at https://doi.org/10.1038/s41586-019-1770-6)
• Elevated X-linked inhibitor of apoptosis protein (XIAP) expression uncovers detrimental prognosis in subgroups of neoadjuvant treated and T-cell rich esophageal adenocarcinoma. BMC Cancer. 2019 May 31;19(1):531
  Schiffmann LM, Göbel H, Löser H, Schorn F, Werthenbach JP, Fuchs HF, Plum PS, Bludau M, Zander T, Schröder W, Bruns CJ, Kashkar H, Quaas A, Gebauer F
  (See online at https://doi.org/10.1186/s12885-019-5722-1)
• Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer. Br J Cancer. 2019 Jan;120(1):69-78
  Schiffmann LM, Fritsch M, Gebauer F, Günther SD, Stair NR, Seeger JM, Thangarajah F, Dieplinger G, Bludau M, Alakus H, Göbel H, Quaas A, Zander T, Hilberg F, Bruns CJ, Kashkar H, Coutelle O
  (See online at https://doi.org/10.1038/s41416-018-0198-3)
• CHIP ubiquitylates NOXA and induces its lysosomal degradation in response to DNA damage. Cell Death Dis. 2020 Sep 10;11(9):740
  Albert MC, Brinkmann K, Pokrzywa W, Günther SD, Krönke M, Hoppe T, Kashkar H
  (See online at https://doi.org/10.1038/s41419-020-02923-x)
• Cytosolic Gramnegative bacteria prevent apoptosis by inhibition of effector caspases through lipopolysaccharide. Nat Microbiol. 2020 Feb;5(2):354-367
  Günther SD, Fritsch M, Seeger JM, Schiffmann LM, Snipas SJ, Coutelle M, Kufer TA, Higgins PG, Hornung V, Bernardini ML, Höning S, Krönke M, Salvesen GS, Kashkar H
  (See online at https://doi.org/10.1038/s41564-019-0620-5)
• An Autochthonous Mouse Model of Myd88- and BCL2-Driven Diffuse Large B-cell Lymphoma Reveals Actionable Molecular Vulnerabilities. Blood Cancer Discov. 2021 Jan;2(1):70-91
  Flümann R, Rehkämper T, Nieper P, Pfeiffer P, Holzem A, Klein S, Bhatia S, Kochanek M, Kisis I, Pelzer BW, Ahlert H, Hauer J, da Palma Guerreiro A, Ryan JA, Reimann M, Riabinska A, Wiederstein J, Krüger M, Deckert M, Altmüller J, Klatt AR, Frenzel LP, Pasqualucci L, Béguelin W, Melnick AM, Sander S, Montesinos-Rongen M, Brunn A, Lohneis P, Büttner R, Kashkar H, Borkhardt A, Letai A, Persigehl T, Peifer M, Schmitt CA, Reinhardt HC, Knittel G
  (See online at https://doi.org/10.1158/2643-3230.bcd-19-0059)
• USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork. Cell Rep. 2021 Oct 12;37(2):109819
  Franz A, Valledor P, Ubieto-Capella P, Pilger D, Galarreta A, Lafarga V, Fernández-Llorente A, de la Vega-Barranco G, den Brave F, Hoppe T, Fernandez-Capetillo O, Lecona E
  (See online at https://doi.org/10.1016/j.celrep.2021.109819)