FBXO31-mediated ubiquitination of OGT maintains <i>O</i>-GlcNAcylation homeostasis to restrain endometrial malignancy

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Abstract

Protein O-GlcNAcylation is a post-translational modification coupled to cellular metabolic plasticity. Aberrant O-GlcNAcylation has been observed in many cancers including endometrial cancer (EC), a common malignancy in women. However, clinical characterization of dysregulated O-GlcNAcylation homeostasis in EC and interrogating its molecular mechanism remain incomplete. Here we report that O-GlcNAcylation level is positively correlated with EC histologic grade in a Chinese cohort containing 219 tumors, validated in The Cancer Genome Atlas dataset. Increasing O-GlcNAcylation in patient-derived endometrial epithelial organoids promotes proliferation and stem-like cell properties, whereas decreasing O-GlcNAcylation limits the growth of endometrial cancer organoids. CRISPR screen and biochemical characterization reveal that tumor suppressor F-box only protein 31 (FBXO31) regulates O-GlcNAcylation homeostasis in EC by ubiquitinating the O-GlcNAc transferase OGT. Downregulation of O-GlcNAcylation impedes EC tumor formation in mouse models. Collectively, our study highlights O-GlcNAcylation as a useful stratification marker and a therapeutic vulnerability for the advanced, poorly differentiated EC cases.

Abstract

Aberrant protein O-GlcNAcylation has been linked with endometrial cancer (EC). Here the authors report that cellular O-GlcNAcylation level is positively correlated with EC histologic grade, and FBXO31 regulates O-GlcNAcylation homeostasis in EC by ubiquitinating the O-GlcNAc transferase OGT.

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Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)

This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.

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Improved vectors and genome-wide libraries for CRISPR screening.

Neville E Sanjana, Ophir Shalem, Feng Zhang (2014)

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An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

Jianfang Liu, Tara M Lichtenberg, Katherine A. Hoadley … (2018)

SUMMARY For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale.

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Author and article information

Contributors

Kai Yuan:

ORCID: http://orcid.org/0000-0001-7002-5703

yuankai@csu.edu.cn

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 2 February 2025

Publication date PMC-release: 2 February 2025

Publication date Collection: 2025

Volume: 16

Electronic Location Identifier: 1274

Affiliations

[1 ]Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology & Department of Gynecology, Xiangya Hospital, Central South University, ( https://ror.org/00f1zfq44) Changsha, 410000 China

[2 ]Center for Medical Genetics, School of Life Sciences, Central South University, ( https://ror.org/00f1zfq44) Changsha, 410008 China

[3 ]School of Pharmaceutical Sciences, Tsinghua University, ( https://ror.org/03cve4549) Beijing, 100084 China

[4 ]Furong Laboratory, Changsha, 410008 China

[5 ]National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, ( https://ror.org/00f1zfq44) Changsha, 410000 China

[6 ]The Biobank of Xiangya Hospital, Central South University, ( https://ror.org/00f1zfq44) Changsha, 410000 China

Author information

Kai Yuan http://orcid.org/0000-0001-7002-5703

Article

Publisher ID: 56633

DOI: 10.1038/s41467-025-56633-z

PMC ID: 11788441

PubMed ID: 39894887

SO-VID: 793aa862-192e-4456-a1ae-bab4a1deefaa

License:

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

History

Date received : 6 March 2024

Date accepted : 24 January 2025

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 92153301

Award ID: 32170821

Award ID: 32370821

Award ID: 32101034

Award Recipient : Fang Chen Kai Yuan

Funded by: National Key Research and Development Program of China (2021YFC2701200), Department of Science & Technology of Hunan Province (grants 2023RC1028, 2023SK2091, and 2021JJ10054 to K.Y).

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Keywords: endometrial cancer,glycosylation

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ScienceOpen disciplines: Uncategorized

Keywords: endometrial cancer, glycosylation

FBXO31-mediated ubiquitination of OGT maintains O-GlcNAcylation homeostasis to restrain endometrial malignancy

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Most cited references 106

Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

Improved vectors and genome-wide libraries for CRISPR screening.

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

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