PMID- 37202505
OWN - NLM
STAT- MEDLINE
DCOM- 20230630
LR  - 20230702
IS  - 1476-5403 (Electronic)
IS  - 1350-9047 (Print)
IS  - 1350-9047 (Linking)
VI  - 30
IP  - 7
DP  - 2023 Jul
TI  - USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in 
      squamous cancer.
PG  - 1710-1725
LID - 10.1038/s41418-023-01173-6 [doi]
AB  - SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic 
      process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol 
      and also provides substrates for protein prenylation. Here, we identify SREBP2 as 
      a novel substrate for USP28, a deubiquitinating enzyme that is frequently 
      upregulated in squamous cancers. Our results show that silencing of USP28 reduces 
      expression of MVP enzymes and lowers metabolic flux into this pathway. We also 
      show that USP28 binds to mature SREBP2, leading to its deubiquitination and 
      stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP 
      inhibition by statins, which was rescued by the addition of geranyl-geranyl 
      pyrophosphate. Analysis of human tissue microarrays revealed elevated expression 
      of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared 
      to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 
      selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of 
      lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 
      inhibitor to reduce viability of SCC cells. Our findings suggest that 
      combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the 
      treatment of squamous cell carcinomas.
CI  - (c) 2023. The Author(s).
FAU - Maier, Carina R
AU  - Maier CR
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
AD  - Protein Stability and Cancer Group, Department of Biochemistry and Molecular 
      Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074, Wurzburg, 
      Germany.
FAU - Hartmann, Oliver
AU  - Hartmann O
AUID- ORCID: 0000-0002-5663-645X
AD  - Protein Stability and Cancer Group, Department of Biochemistry and Molecular 
      Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074, Wurzburg, 
      Germany.
FAU - Prieto-Garcia, Cristian
AU  - Prieto-Garcia C
AUID- ORCID: 0000-0002-7576-1061
AD  - Protein Stability and Cancer Group, Department of Biochemistry and Molecular 
      Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074, Wurzburg, 
      Germany.
AD  - Institute of Biochemistry II, Goethe University Frankfurt, Theodor-Stern-Kai 7, 
      Haus 75, 60590, Frankfurt am Main, Germany.
FAU - Al-Shami, Kamal M
AU  - Al-Shami KM
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
FAU - Schlicker, Lisa
AU  - Schlicker L
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
FAU - Vogel, Felix C E
AU  - Vogel FCE
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
FAU - Haid, Silke
AU  - Haid S
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany.
FAU - Klann, Kevin
AU  - Klann K
AD  - Institute of Biochemistry II, Goethe University Frankfurt, Theodor-Stern-Kai 7, 
      Haus 75, 60590, Frankfurt am Main, Germany.
FAU - Buck, Viktoria
AU  - Buck V
AD  - Institute of Pathology, Julius Maximilians University and Comprehensive Cancer 
      Center (CCC) Mainfranken, Josef-Schneider-Strasse 2, 97080, Wurzburg, Germany.
FAU - Munch, Christian
AU  - Munch C
AUID- ORCID: 0000-0003-3832-090X
AD  - Institute of Biochemistry II, Goethe University Frankfurt, Theodor-Stern-Kai 7, 
      Haus 75, 60590, Frankfurt am Main, Germany.
FAU - Schmitz, Werner
AU  - Schmitz W
AD  - Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, 
      Biocenter, University of Wurzburg, 97074, Wurzburg, Germany.
FAU - Einig, Elias
AU  - Einig E
AUID- ORCID: 0000-0001-7142-1281
AD  - Internal Medicine VIII-Clinical Tumor Biology, University of Tubingen, 
      Otfried-Muller-Strasse 14, 72076, Tubingen, Germany.
FAU - Krenz, Bastian
AU  - Krenz B
AUID- ORCID: 0000-0003-1889-3022
AD  - Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, 
      Biocenter, University of Wurzburg, 97074, Wurzburg, Germany.
FAU - Calzado, Marco A
AU  - Calzado MA
AUID- ORCID: 0000-0002-5338-535X
AD  - Instituto Maimonides de Investigacion Biomedica de Cordoba (IMIBIC), Cordoba, 
      Spain.
AD  - Departamento de Biologia Celular, Fisiologia e Inmunologia, Universidad de 
      Cordoba, Cordoba, Spain.
AD  - Hospital Universitario Reina Sofia, Cordoba, Spain.
FAU - Eilers, Martin
AU  - Eilers M
AUID- ORCID: 0000-0002-0376-6533
AD  - Theodor Boveri Institute, Department of Biochemistry and Molecular Biology, 
      Biocenter, University of Wurzburg, 97074, Wurzburg, Germany.
FAU - Popov, Nikita
AU  - Popov N
AD  - Internal Medicine VIII-Clinical Tumor Biology, University of Tubingen, 
      Otfried-Muller-Strasse 14, 72076, Tubingen, Germany.
FAU - Rosenfeldt, Mathias T
AU  - Rosenfeldt MT
AUID- ORCID: 0000-0001-7650-8458
AD  - Institute of Pathology, Julius Maximilians University and Comprehensive Cancer 
      Center (CCC) Mainfranken, Josef-Schneider-Strasse 2, 97080, Wurzburg, Germany.
FAU - Diefenbacher, Markus E
AU  - Diefenbacher ME
AUID- ORCID: 0000-0002-7402-7949
AD  - Protein Stability and Cancer Group, Department of Biochemistry and Molecular 
      Biology, Theodor-Boveri-Institute, Biocenter, Am Hubland, 97074, Wurzburg, 
      Germany. markus.diefenbacher@uni-wuerzburg.de.
FAU - Schulze, Almut
AU  - Schulze A
AUID- ORCID: 0000-0002-8199-6422
AD  - German Cancer Research Center, Division of Tumor Metabolism and Microenvironment, 
      Im Neuenheimer Feld 581, 69120, Heidelberg, Germany. 
      almut.schulze@dkfz-heidelberg.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230518
PL  - England
TA  - Cell Death Differ
JT  - Cell death and differentiation
JID - 9437445
RN  - S5UOB36OCZ (Mevalonic Acid)
RN  - 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors)
RN  - EC 3.4.19.12 (Ubiquitin Thiolesterase)
RN  - 0 (USP28 protein, human)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Humans
MH  - Mevalonic Acid/metabolism
MH  - *Hydroxymethylglutaryl-CoA Reductase Inhibitors
MH  - *Carcinoma, Non-Small-Cell Lung
MH  - *Lung Neoplasms/genetics
MH  - *Carcinoma, Squamous Cell/genetics
MH  - Ubiquitin Thiolesterase/metabolism
PMC - PMC10307777
COIS- The authors declare no competing interests.
EDAT- 2023/05/19 01:04
MHDA- 2023/06/30 06:42
PMCR- 2023/05/18
CRDT- 2023/05/18 23:21
PHST- 2022/12/20 00:00 [received]
PHST- 2023/04/25 00:00 [accepted]
PHST- 2023/04/16 00:00 [revised]
PHST- 2023/06/30 06:42 [medline]
PHST- 2023/05/19 01:04 [pubmed]
PHST- 2023/05/18 23:21 [entrez]
PHST- 2023/05/18 00:00 [pmc-release]
AID - 10.1038/s41418-023-01173-6 [pii]
AID - 1173 [pii]
AID - 10.1038/s41418-023-01173-6 [doi]
PST - ppublish
SO  - Cell Death Differ. 2023 Jul;30(7):1710-1725. doi: 10.1038/s41418-023-01173-6. 
      Epub 2023 May 18.