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USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma

Oncogene volume 41, pages 5061–5075 (2022)Cite this article

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Abstract

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific target protein substrates in order to alter their degradation rate, sub-cellular localization, interaction, and activity. The induction of apoptosis upon USP7 inhibition is well established in cancer containing wild type p53, which operates through the ‘USP7-Mdm2-p53’ axis. However, in cancers without functional p53, USP7-dependent apoptosis is induced through many other alternative pathways. Here, we have identified another critical p53 independent path active under USP7 to regulate apoptosis. Proteomics analysis identifies XIAP as a potential target of USP7-dependent deubiquitination. GSEA analysis revealed up-regulation of apoptosis signalling upon USP7 inhibition associated with XIAP down-regulation. Modulation of USP7 expression and activity in multiple cancer cell lines showed that USP7 deubiquitinates XIAP to inhibit apoptosis in a caspase-dependent pathway, and the combinatorial inhibition of USP7 and XIAP induces apoptosis in vitro and in vivo. Immunohistochemical staining revealed that grade-wise accumulation of USP7 correlated with an elevated level of XIAP in glioma tissue. This is the first report on the identification and validation of XIAP as a novel substrate of USP7 and together, they involve in the empowerment of the tumorigenic potential of cancer cells by inhibiting apoptosis.

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Fig. 1: p53 independent apoptosis uponUSP7 inhibition: XIAP is a possible mediator.
Fig. 2: XIAP: a putative substrate of USP7.
Fig. 3: XIAP and USP7 colocalize and physically interact.
Fig. 4: USP7 protects XIAP from ubiquitination-dependent degradation in p53 independent manner.
Fig. 5: USP7 regulates cellular fate through involvement of XIAP.
Fig. 6: USP7 and XIAP clinically correlated in glioma.
Fig. 7: USP7—XIAP axis is important in tumor progression.
Fig. 8: Proposed model: USP7 deubiquitinates and stabilizes anti-apoptotic protein XIAP and promotes cancer cell survival.

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Data availability

Data supporting the conclusion of the current study is included in the manuscript and the supplementary files.

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Acknowledgements

We sincerely thanks to Dr. Sandip Chatterjee (PARK Clinic, Kolkata) for scientific discussion and Mr. Pratyay Ghosh, Department of Electronics and Instrumentation Engineering, Techno India College, Kolkata for editing the manuscript. We also thanks to Mr. Bhaskar Basu and Ms. Srija Roy (CSIR-IICB) for technical assistance.

Funding

This work is jointly supported by the Department of Science and Technology (NanoMission: DST/NM/NT/2018/105(G); SERB: EMR/2017/000992) and Focused Basic Research (FBR #31-2(274)2020-21/Bud-II), HCT & HCP-40, CSIR, Govt. of India.

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Authors and Affiliations

  1. Cancer Biology & Inflammatory Disorder Division, Council of Scientific and Industrial Research-Indian Institute of Chemical Biology (CSIR-IICB), TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata- 700091 & 4, Raja S.C. Mullick Road, Jadavpur, Kolkata, 700032, India

    Gouranga Saha, Sibani Sarkar, Partha S. Mohanta & Mrinal K. Ghosh

  2. Structural Biology & Bioinformatics Division, CSIR-IICB, TRUE Campus, CN-6, Sector–V, Salt Lake, Kolkata, 700091, India

    Krishna Kumar & Saikat Chakrabarti

  3. Department of Microbiology, Dhruba Chand Halder College, South 24 Paraganas, PIN -743372, Dakshin Barasat, West Bengal, India

    Malini Basu

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  1. Gouranga Saha
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Contributions

GS and MKG conceptualised the study, designed and analyzed the data. GS performed most of the experiments, data acquisition, and statistical analyses. GS and PM performed animal experiments (Fig. 7) under the guidance of SS and MKG. KK performed the bioinformatic analyses (Fig. 3G, H) under the guidance of SC. GS, KK, MB and MKG wrote and edited the manuscript.

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Correspondence to Mrinal K. Ghosh.

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Saha, G., Sarkar, S., Mohanta, P.S. et al. USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma. Oncogene 41, 5061–5075 (2022). https://doi.org/10.1038/s41388-022-02486-5

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