Abstract
Background
Ubiquitin-specific protease 22 (USP22) has been implicated in the progression of breast
cancer, while its regulatory functions in triple-negative breast cancer (TNBC) have
been rarely reported. This study aimed to elucidate the effect and mechanism of USP22
on the malignant phenotype of TNBC cells.
Materials and Methods
The expression of USP22, stemness genes, and EMT-related markers were analyzed by
RT-qPCR and/or Western blotting. Cell stemness was determined by cell spheroid formation,
flow cytometry for CD44+/CD24-, and extreme limiting dilution analysis. Cell proliferation
and cisplatin (DDP) chemoresistance of TNBC cells were assessed by CCK-8 assay and
xenograft model. Glycolysis was measured by Seahorse assay. The mechanism underlying
the role of USP22 was explored by Co-immunoprecipitation, ubiquitination assay, and
cycloheximide-chase analysis.
Results
USP22 expression was positively correlated with DDP resistance in TNBC patients and
cells. The proliferation, spheroid number, CD44+/CD24- cells, the expression of stemness
genes and EMT-related markers in TNBC cells were significantly elevated after USP22
was overexpressed; however, these parameters in DDP-resistant TNBC (TNBC/DDP) cells
were significantly reduced after silencing USP22. USP22 overexpression enhanced the
extracellular acidification rate, proliferation, spheroid number, CD44+/CD24- cell
number, and the expression of stemness genes and EMT-related markers in TNBC/DDP cells,
while these effects were restrained by glycolysis inhibitors. Mechanically, USP22
interacted with c-Myc to promote its stabilization by deubiquitination in TNBC cells.
Silencing of USP22 increased DDP sensitivity and survival of mice bearing TNBC.
Conclusion
USP22 contributes to chemoresistance, stemness, and EMT phenotype of TNBC cells by
suppressing the glycolysis via c-Myc deubiquitination.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Breast CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A. and Bray F. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 Cancers in 185 Countries.CA Cancer J Clin. 2021; 71: 209-249
- Triple-negative breast cancer.N Engl J Med. 2010; 363: 1938-1948
- Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies.J Clin Invest. 2011; 121: 2750-2767
- Cancer stem cells: an evolving concept.Nat Rev Cancer. 2012; 12: 133-143
- Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.Nat Commun. 2018; 9: 2897
- Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells.Nature. 2015; 526: 131-135
- Targeting the roots of recurrence: new strategies for eliminating therapy-resistant Breast Cancer Stem Cells.Cancers (Basel). 2020; 13
- Metabolic reprogramming and cancer progression.Science. 2020; 368
- The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth.Nature. 2008; 452: 230-233
- Understanding the Warburg effect: the metabolic requirements of cell proliferation.Science. 2009; 324: 1029-1033
- Tumor-secreted dickkopf2 accelerates aerobic glycolysis and promotes angiogenesis in colorectal cancer.Theranostics. 2019; 9: 1001-1014
- CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1α axis to inhibit gastric tumorigenesis.Oncogene. 2018; 37: 6383-6398
- Metabolic reprogramming in cancer: role of HPV 16 variants.Pathogens. 2021; 2021: 10
- Targeting cancer metabolism: a therapeutic window opens.Nat Rev Drug Discov. 2011; 10: 671-684
- MYC-induced cancer cell energy metabolism and therapeutic opportunities.Clin Cancer Res. 2009; 15: 6479-6483
- MYC on the path to cancer.Cell. 2012; 149: 22-35
- USP22 exerts tumor-suppressive functions in colorectal cancer by decreasing mTOR activity.Cell Death Differ. 2020; 27: 1328-1340
- USP22 promotes hypoxia-induced hepatocellular carcinoma stemness by a HIF1α/USP22 positive feedback loop upon TP53 inactivation.Gut. 2020; 69: 1322-1334
- USP22 regulates oncogenic signaling pathways to drive lethal cancer progression.Cancer Res. 2014; 74: 272-286
- Aberrant expression of USP22 is associated with liver metastasis and poor prognosis of colorectal cancer.J Surg Oncol. 2011; 103: 283-289
- Hypoxia-induced USP22-BMI1 axis promotes the stemness and malignancy of glioma stem cells via regulation of HIF-1α.Life Sci. 2020; 247: 117438
- Elevated expression of USP22 in correlation with poor prognosis in patients with invasive breast cancer.J Cancer Res Clin Oncol. 2011; 137: 1245-1253
- USP22 promotes HER2-driven mammary carcinoma aggressiveness by suppressing the unfolded protein response.Oncogene. 2021; 40: 4004-4018
- Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.Methods. 2001; 25: 402-408
- Novel strategies to target chemoresistant triple-negative breast cancer.Genes Cancer. 2020; 11: 95-105
- ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays.J Immunol Methods. 2009; 347: 70-78
- New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer. 2009; 45: 228-247
- EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer.Oncogene. 2010; 29: 4741-4751
- STAT3 as a promising chemoresistance biomarker associated with the CD44(+/high)/CD24(-/low)/ALDH(+) BCSCs-like subset of the triple-negative breast cancer (TNBC) cell line.Exp Cell Res. 2018; 363: 283-290
- Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities.Cancer Metab. 2017; 5: 6
- Ubiquitin-specific peptidase 22 in cancer.Cancer Lett. 2021; 514: 30-37
- Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy.Breast Cancer Res. 2008; 10: R25
- Eradication of cancer stem cells in triple negative breast cancer using doxorubicin/pluronic polymeric micelles.Nanomedicine. 2020; 24: 102124
- Expression patterns of USP22 and potential targets BMI-1, PTEN, p-AKT in non-small-cell lung cancer.Lung Cancer. 2012; 77: 593-599
- Significance of CD44 and CD24 as cancer stem cell markers: an enduring ambiguity.Clin Dev Immunol. 2012; 2012708036
- EMT Transition States during Tumor Progression and Metastasis.Trends Cell Biol. 2019; 29: 212-226
- Epithelial-to-mesenchymal transition in cancer: complexity and opportunities.Front Med. 2018; 12: 361-373
- USP22 promotes tumor progression and induces epithelial-mesenchymal transition in lung adenocarcinoma.Lung Cancer. 2015; 88: 239-245
- Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma.Cell Death Dis. 2021; 12: 678
- Interplay between Metabolism Reprogramming and Epithelial-to-Mesenchymal Transition in Cancer Stem Cells.Cancers (Basel). 2021; 13
- Stress-induced epinephrine enhances lactate dehydrogenase A and promotes breast cancer stem-like cells.J Clin Invest. 2019; 129: 1030-1046
- Glucose oxidation modulates anoikis and tumor metastasis.Mol Cell Biol. 2012; 32: 1893-1907
- Ketones and lactate increase cancer cell “stemness,” driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics.Cell Cycle. 2011; 10: 1271-1286
- USP22 Deubiquitinates CD274 to suppress anticancer immunity.Cancer Immunol Res. 2019; 7: 1580-1590
- USP22 acts as an oncogene by regulating the stability of cyclooxygenase-2 in non-small cell lung cancer.Biochem Biophys Res Commun. 2015; 460: 703-708
- MYC, metabolism, cell growth, and tumorigenesis.Cold Spring Harb Perspect Med. 2013; 3
- LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc.Nat Commun. 2019; 10: 3499
- mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc.Cell Metab. 2013; 18: 726-739
- Deubiquitinating enzyme USP22 positively regulates c-Myc stability and tumorigenic activity in mammalian and breast cancer cells.J Cell Physiol. 2017; 232: 3664-3676
Article info
Publication history
Published online: November 24, 2022
Accepted:
November 22,
2022
Received in revised form:
November 7,
2022
Received:
July 1,
2022
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
