Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis

Kun Liu; Qiong Gao; Yuzhi Jia; Juncheng Wei; Shuvam Mohan Chaudhuri; Shengnan Wang; Amy Tang; Nikita Lavanya Mani; Radhika Iyer; Yang Cheng; Beixue Gao; Weiyuan Lu; Zhaolin Sun; Bin Zhang; Huiping Liu; Deyu Fang

doi:10.1016/j.isci.2024.110592

Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis

Kun Liu, Qiong Gao, Yuzhi Jia, Juncheng Wei, Shuvam Mohan Chaudhuri, Shengnan Wang, Amy Tang, Nikita Lavanya Mani, Radhika Iyer, Yang Cheng, Beixue Gao, Weiyuan Lu, Zhaolin Sun, Bin Zhang, Huiping Liu, Deyu Fang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

2 Scopus citations

Abstract

Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.

Original language	English (US)
Article number	110592
Journal	iScience
Volume	27
Issue number	9
DOIs	https://doi.org/10.1016/j.isci.2024.110592
State	Published - Sep 20 2024

Funding

We thank the Northwestern Lurie Cancer Center flow cytometry core for their service support. We thank Dr. Liping Jiang from the University of Illinois at Chicago for conducting the Dual-luciferase reporter assay. This work was supported by National Institutes of Health grants R01DK126908, R01DK120330, R01CA257520, and CA232347 (to D.F.), R01CA245699 and UG3CA256967 (to H.L.), National Natural Science Foundation of China (no.82073768) and Dalian High-level Talent Innovation Support Program (no. 2019RD03) to Z.S. Department of Defense Breast Cancer Research Program W81XWH2010679 (to H.L), and Lynn Sage Breast Cancer Foundation (D.F. and H.L.). D.F. designed and supervised this study and wrote the manuscript. K.L. performed most of the experiments and wrote the manuscript. Q.G. developed the concepts and assisted with K.L. in this study. H.L. and Y. J. provided breast cancer patient-derived xenograft models. J.W. and Y. J. helped with the animal studies. A.T. and N.L.M. helped with the flow cytometry experiments, R.I, B.G. W.L. and Z.S. helped with the data analysis. H.L. S.M.C. A.T. B.Z. and R.I. edited the manuscript. Drs. Deyu Fang and Huiping Liu are co-founders and equity owners of ExoMira Medicine Inc. Dr. Fang is the inventor of USP22 inhibitor-S02 (patent #: 63/201330).

Keywords

Cancer
Cell biology
Molecular biology

ASJC Scopus subject areas

General

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2024.110592

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title = "Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis",

abstract = "Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.",

keywords = "Cancer, Cell biology, Molecular biology",

author = "Kun Liu and Qiong Gao and Yuzhi Jia and Juncheng Wei and Chaudhuri, {Shuvam Mohan} and Shengnan Wang and Amy Tang and Mani, {Nikita Lavanya} and Radhika Iyer and Yang Cheng and Beixue Gao and Weiyuan Lu and Zhaolin Sun and Bin Zhang and Huiping Liu and Deyu Fang",

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doi = "10.1016/j.isci.2024.110592",

language = "English (US)",

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AU - Liu, Kun

AU - Gao, Qiong

AU - Jia, Yuzhi

AU - Wei, Juncheng

AU - Chaudhuri, Shuvam Mohan

AU - Wang, Shengnan

AU - Tang, Amy

AU - Mani, Nikita Lavanya

AU - Iyer, Radhika

AU - Cheng, Yang

AU - Gao, Beixue

AU - Lu, Weiyuan

AU - Sun, Zhaolin

AU - Zhang, Bin

AU - Liu, Huiping

AU - Fang, Deyu

PY - 2024/9/20

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N2 - Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.

AB - Integrins play critical roles in connecting the extracellular matrix and actin. While the upregulation of integrins is thought to promote cancer stemness and metastasis, the mechanisms underlying their upregulation in cancer stem cells (CSCs) remain poorly understood. Herein, we show that USP22 is essential in maintaining breast cancer cell stemness by promoting the transcription of integrin β1 (ITGB1). Both genetic and pharmacological inhibition of USP22 largely impaired breast CSCs self-renewal and prevented their metastasis. Reconstitution of integrin β1 partially rescued USP22-null breast cancer metastasis. USP22 functions as a bona fide deubiquitinase to protect the proteasomal degradation of the forkhead box M1 (FoxM1), a transcription factor for tumoral ITGB1 gene transcription. Immunohistochemistry staining detected a positive correlation among USP22, FoxM1, and integrin β1 in human breast cancers. Collectively, our study identifies the USP22-FoxM1-integrin β1 signaling axis as critical for cancer stemness and offers a potential target for antitumor therapy.

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Ubiquitin-specific peptidase 22 controls integrin-dependent cancer cell stemness and metastasis

Abstract

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