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Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis

Oncogene volume 41, pages 46–56 (2022)Cite this article

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Abstract

Aberrant regulation of ubiquitination often leads to metabolic reprogramming in tumor cells. However, the underlying mechanisms are not fully understood. Here we demonstrate that OTUB2, an OTU deubiquitinase, is upregulated in colorectal cancer (CRC) and exacerbates the progression of CRC through modulating the aerobic glycolysis. Mechanistically, OTUB2 directly interacts with pyruvate kinase M2 (PKM2) and inhibits its ubiquitination by blocking the interaction between PKM2 and its ubiquitin E3 ligase Parkin, thereby enhancing PKM2 activity and promoting glycolysis. In response to glucose starvation stress, the effect of OTUB2 on PKM2 is enhanced, which confers metabolic advantage to CRC cells. Moreover, OTUB2 depletion reduces glucose consumption, lactate production, and cellular ATP production. OTUB2-knockout CRC cells exhibit attenuated proliferation and migration, as well as an elevated level of apoptosis and increased sensitivity to chemotherapy drugs. Furthermore, in vivo assays show that knockout of OTUB2 inhibits tumor growth in mice. Taken together, these findings reveal the critical role of OTUB2 in the regulation of glycolysis and illustrate the molecular mechanism underlying its role as a negative regulator of PKM2 ubiquitination in CRC, establishing a bridge between OTUB2-regulated PKM2 ubiquitination and altered metabolic patterns in CRC and suggesting that OTUB2 is a promising target for CRC treatment.

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Fig. 1: OTUB2 is highly expressed in CRC.
Fig. 2: OTUB2 interacts and colocalizes with PKM2.
Fig. 3: OTUB2 downregulates the ubiquitination of PKM2.
Fig. 4: OTUB2 inhibits ubiquitination of PKM2 by antagonizing the PKM2-Parkin interaction.
Fig. 5: OTUB2 enhances PKM2 metabolic enzymatic activity and glycolysis.
Fig. 6: OTUB2 promotes the development of CRC.
Fig. 7: A proposed model for OTUB2-mediated PKM2 deubiquitination in CRC.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (grant nos. 81730080 and 82130081), Beijing Natural Science Foundation (5212008), and the National Key Research and Development Program of China (grant no. 2016YFC1302401). We sincerely thank Prof. Lingqiang Zhang for providing human deubiquitinase OTU subfamily plasmids, Prof. Wensheng Wei for providing the CRISPR/Cas9 related plasmids, Prof. Jianguo Ji for providing HT-29 cell line, Prof. Dajun Deng for providing CCD-18Co cell line, Prof. Binghui Li for providing FHC cell line, and Prof. Zhijie Chang for providing NCM460 and DLD-1 cell lines. We thank the National Center for Protein Sciences at Peking University, particularly Guilan Li, Jia Luo, Yinghua Guo, Liying Du and Hongxia Lv for technical help. We also appreciate the assistance of Dong Liu, Xiaochen Li and Liqin Fu from the Core Facilities of Life Sciences at Peking University for their assistance with the protein MS analysis work and microscopic imaging.

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  1. State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China

    Shuyu Yu, Weicheng Zang, Yuchong Qiu, Liming Liao & Xiaofeng Zheng

  2. Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China

    Shuyu Yu, Weicheng Zang, Yuchong Qiu, Liming Liao & Xiaofeng Zheng

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  1. Shuyu Yu
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SY designed the experiments, analyzed the data, and wrote the manuscript. SY, WZ, and LL performed the experiments. YQ and SY performed the bioinformatics analysis. XZ supervised this study and wrote the manuscript.

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Correspondence to Xiaofeng Zheng.

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Yu, S., Zang, W., Qiu, Y. et al. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. Oncogene 41, 46–56 (2022). https://doi.org/10.1038/s41388-021-02071-2

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