Abstract
Cancer cells undergo complex metabolic alterations. The mechanisms underlying the tuning of cancer metabolism are under active investigation. Here, we identify the uncharacterized deubiquitinase JOSD2 as a positive regulator of cancer cell proliferation by displaying comprehensive effects on glucose catabolism. We found that JOSD2 directly controls a metabolic enzyme complex that includes Aldolase A, Phosphofructokinase-1 and Phosphoglycerate dehydrogenase, in vitro and in vivo. Further, JOSD2 expression, but not a catalytically inactive mutant, deubiquitinates and stabilizes the enzyme complex, thereby enhancing their activities and the glycolytic rate. This represents a selective JOSD2 feature that is not shared among other Machado–Joseph disease DUBs or observed in nontransformed cells. JOSD2 deficiency displays cytostatic effects and reduces glycolysis in a broad spectrum of tumor cells of distinct origin and its expression correlates with poor prognosis in non-small cell lung cancer. Overall, our study provides evidence for a previously unknown biological mechanism in which JOSD2 integrates glucose and serine metabolism with potential therapeutic implications.
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Acknowledgements
This work was supported by grants from The Swedish Research Council (VR), The Swedish Cancer Society (Cancerfonden), Ragnar Söderbergs Stiftelse, Stiftelsen Lars Hiertas Minne, Stiftelsen Längmanska Kulturfonden, and the Karolinska Institute Tenure Track Research grants. We thank Dr. Yuqing Hao for advice on the mutagenesis. We thank Drs. Tsutomu Hoshiba and Laura Shelton (Human Metablome Technilogies) for the isotopomer and metabolome studies. We thank Drs. Mandy Rettel and Frank Stein (EMBL proteomics facility) for the quantitative proteomics.
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LK performed isotopomer labeling, ECAR analyses, OCR for HAP and A549 cell lines. BZ performed bioinformatics, pathway, and the statistical analysis of proteomics data. LK and DN performed the western blots, qPCR, and enzymatic activity assays. DN performed immunoprecipitations, deubiquitination assays, cell growth, and experiments with HAP cells. ALQ performed OCR of A549 cells for the initial submission, MK performed mutagenesis and qPCR, and ES performed fractionation. HVN provided critical advice and reagents. EN, HVN, LK, BZ, and DN wrote the original manuscript with input from all authors. LK, BZ, DN, and EN prepared the figures. All authors analyzed and interpreted data. LK, DN, and MK performed the revision and editing. EN designed, supervised, and financed the research.
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Krassikova, L., Zhang, B., Nagarajan, D. et al. The deubiquitinase JOSD2 is a positive regulator of glucose metabolism. Cell Death Differ 28, 1091–1109 (2021). https://doi.org/10.1038/s41418-020-00639-1
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DOI: https://doi.org/10.1038/s41418-020-00639-1
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